Substituted pyrrolo-pyrazole derivatives as kinase inhibitors

ABSTRACT

Substituted pyrrolo-pyrazole derivatives of formula (I) and pharmaceutically acceptable salts thereof, as defined in the specification, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful in therapy in the treatment of diseases associated with dysregulated protein kinase activity, like cancer.

The present invention relates to certain substituted pyrrolo-pyrazolecompounds, which modulate the activity of protein kinases. The compoundsof this invention are therefore useful in treating diseases caused bydysregulated protein kinase activity. The present invention alsoprovides methods for preparing these compounds, pharmaceuticalcompositions comprising these compounds, and methods of treatingdiseases utilizing pharmaceutical compositions comprising thesecompounds.

The use of mitotic inhibitors in cancer therapy is a widely acceptedclinical strategy for the treatment of a broad range of human cancers.Taxanes (Paclitaxel and Docetaxel) and Vinca Alkaloids (Vincristine andVinblastine) work by either stabilizing or destabilizing microtubuleswith catastrophic consequences in cells progressing through mitosis.They are first line therapeutics for several tumour types and secondline in cisplatin-refractory Ovarian, Breast, Lung, bladder andesophagus cancers (Taxanes). However, due to the role of microtubules inprocesses such as cell movement, phagocytosis and axonal transportcertain toxicities such as peripheral neuropathy are frequently observedwith these agents. Progression through mitosis is a requirement of allproliferating cells and hence cancer therapies that have targets inmitosis are generally applicable to a wide range of tumour types.Several protein kinases play key roles in the orchestration of the cellcycle and some of them are already subject to targeted therapies in theoncology setting including Cdk-2 and Aurora-A. The fidelity of mitosisis of paramount importance and several “checkpoints” exist in normalcells to maintain chromosome integrity during the cell cycle. Thesecheckpoints often go away during oncogenic transformation and thispermits cancer cells to tolerate anueploidy and chromosomal instability.Inhibition of mitosis in “checkpoint compromised” tumour cells shouldhave catastrophic consequences as cancer cells try to carry forward anaberrant mitosis.

The Polo-like kinase family, comprising 4 serine/threonine kinases(Plk-1-4), are predominantly involved in the entry into, progressionthrough and exit from mitosis. These kinases are characterized by havingan n-terminal kinase domain and a unique, c-terminal, “Polo-Box” domain.This domain is responsible for targeting the kinase to various mitoticstructures (centrosomes, kinetochores, spindle poles, midbody) and thetemporal and spatial regulation of Plks are important for normalprogression through mitosis (reviewed in van Vugt and Medema, Oncogene2005, 24(17):2844-59; Barr et al, Nat Rev Mol Cell Biol. 2004,5(6):429-40; Dai and Cogswell, Prog Cell Cycle Res. 2003, 5:327-34;Glover et al, Genes Dev. 1998, 12(24):3777-87). The most characterizedmember of the family is Plk-1 and its activity has been implicated inseveral processes during mitosis including the G2/M transition byregulating Cdk-1 activity in multiple ways (activation of Cdc25c,nuclear translocation of cyclin B, inactivation of Myt-1 and Wee-1)(Inoue et al, EMBO J. 2005, 24(5):1057-67; van Vugt et al, J Biol Chem.2004, 9(35):36841-54; Watanabe et al, Proc Natl Acad Sci USA. 2004,101(13):4419-24 2004; Nakajima et al, J Biol Chem. 2003,278(28):25277-80; Toyoshima-Morimoto et al, J Biol Chem. 2002,277(50):48884-8; Bartholomew et al, Mol Cell Biol., 2001 21(15):4949-59;Qian et al, Mol Biol Cell. 2001, 12(6):1791-9; Roshak et al, CellSignal. 2000, 12(6):405-11); centrosome maturation and separation;regulation of chromosomal-arm cohesion at prophase and sister chromatidseparation at metaphase/anaphase transition; activation of the AnaphasePromoting Complex to start mitotic exit; cytokinesis. Plk-1 isover-expressed in several tumour cells including breast, ovarian, nonsmall cell lung, colon, head and neck, endometrial and esophagealcarcinomas and its over-expression often correlates with poor prognosis.

Disruption of Plk-1 function by various means in tumoural cells (siRNAand antisense ablation, dominant negative proteins and immunodepletion)results in an aberrant mitosis followed by mitotic catastrophy whilstcausing a “checkpoint-mediated” cell cycle arrest in normal cells. Thus,pharmacological attenuation of Plk-1 function may have a therapeuticbenefit in the treatment of several diverse cancers.

SUMMARY OF THE INVENTION

Several heterocyclic compounds are known in the art as protein kinaseinhibitors for the treatment of hyperproliferative diseases such as forthe treatment of cancer. As an example, 2-carboxamido-pyrazoles and2-ureido-pyrazoles, and derivatives thereof, have been disclosed asprotein kinase inhibitors in the international patent applications WO01/12189, WO 01/12188, WO 02/48114 and WO 02/70515 (Pfizer Italia Srl).

Fused bicyclic compounds comprising pyrazole moieties and possessingkinase inhibitory activity have been also disclosed in WO 00/69846, WO02/12242, WO 03/28720 and W004/56827 (Pfizer Italia Srl).

Some specific compounds of the aforementioned WO 02/12242 are excludedfrom the present general formula.

Despite these developments, there is still need for effective agents forsaid disease.

The present inventors have now discovered that compounds of formula (I),described below, are kinase inhibitors and are thus useful in therapy asantitumor agents and lack, in terms of both toxicity and side effects,the aforementioned drawbacks associated with currently availableantitumor drugs.

Accordingly, a first object of the present invention is to provide asubstituted pyrrolo-pyrazole compound represented by formula (I),

wherein

R is hydrogen or an optionally further substituted group selected from:saturated or unsaturated, straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, heterocyclyl and aryl;

A is CH₂ or NH;

Ar is an optionally substituted aryl, provided that

when A is CH₂ and Ar is phenyl then R is other than 3-bromophenyl,4-fluorophenyl, 4-tert-butylphenyl, cyclopropyl or 2-naphthyl and

when A is CH₂ and Ar is thiophene then R is other than 3-bromophenyl,4-fluorophenyl, 4-tert-butylphenyl, cyclopropyl, 2-naphthyl or benzyl;and

isomers, tautomers, hydrates, solvates, complexes, metabolites,prodrugs, carriers, N-oxides and pharmaceutically acceptable saltsthereof.

The present invention also provides methods of synthesizing thesubstituted pyrrolo pyrazole derivatives of formula (I) prepared througha process consisting of standard synthetic transformations.

The present invention also provides a method for treating diseasescaused by and/or associated with dysregulated protein kinase activity,particularly PLK family, protein kinase C in different isoforms, Met,PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, Chk1,Chk2, HER2, raf1, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, PI3K, weelkinase, Src, Abl, Akt, MAPK, ILK, MK-2, IKK-2, Cdc7, Nek, Cdk/cyclinkinase family, more particularly PLK-1 and PLK-3, which comprisesadministering to a mammal in need thereof an effective amount of asubstituted pyrrolo-pyrazole compound represented by formula (I) asdefined above.

A preferred method of the present invention is to treat a disease causedby and/or associated with dysregulated protein kinase activity selectedfrom the group consisting of cancer, cell proliferative disorders, viralinfections, autoimmune and neurodegenerative disorders.

Another preferred method of the present invention is to treat specifictypes of cancer including but not limited to: carcinoma such as bladder,breast, colon, kidney, liver, lung, including small cell lung cancer,esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid,prostate, and skin, including squamous cell carcinoma; hematopoietictumors of lymphoid lineage including leukaemia, acute lymphociticleukaemia, acute lymphoblastic leukaemia, B-cell lymphoma,T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma and Burkett's lymphoma; hematopoietic tumors of myeloidlineage, including acute and chronic myelogenous leukemias,myelodysplastic syndrome and promyelocytic leukaemia; tumors ofmesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumorsof the central and peripheral nervous system, including astrocytomaneuroblastoma, glioma and schwannomas; other tumors, including melanoma,seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum,keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma.

Another preferred method of the present invention is to treat specificcellular proliferation disorders such as, for example, benign prostatehyperplasia, familial adenomatosis polyposis, neurofibromatosis,psoriasis, vascular smooth cell proliferation associated withatherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis andpost-surgical stenosis and restenosis.

Another preferred method of the present invention is to treat viralinfections, in particular the prevention of AIDS development inHIV-infected individuals.

In addition, the method of the present invention also provides tumorangiogenesis and metastasis inhibition as well as the treatment of organtransplant rejection and host versus graft disease.

The present invention also provides a pharmaceutical compositioncomprising one or more compounds of formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable excipient,carrier or diluent.

The present invention further provides a pharmaceutical compositioncomprising a compound of formula (I) in combination with knownanticancer treatments such as radiation therapy or chemotherapy regimenin combination with cytostatic or cytotoxic agents, antibiotic-typeagents, alkylating agents, antimetabolite agents, hormonal agents,immunological agents, interferon-type agents, cyclooxygenase inhibitors(e.g. COX-2 inhibitors), matrixmetalloprotease inhibitors, telomeraseinhibitors, tyrosine kinase inhibitors, anti-growth factor receptoragents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents(e.g. angiogenesis inhibitors), farnesyl transferase inhibitors, ras-rafsignal transduction pathway inhibitors, cell cycle inhibitors, othercdks inhibitors, tubulin binding agents, topoisomerase I inhibitors,topoisomerase II inhibitors, and the like.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified, when referring to the compounds of formula(I) per se as well as to any pharmaceutical composition thereof or toany therapeutic treatment comprising them, the present inventionincludes all of the hydrates, solvates, complexes, metabolites,prodrugs, carriers, N-oxides and pharmaceutically acceptable salts ofthe compounds of this invention.

A metabolite of a compound of formula (I) is any compound into whichthis same compound of formula (I) is converted in vivo, for instanceupon administration to a mammal in need thereof. Typically, withouthowever representing a limiting example, upon administration of acompound of formula (I), this same derivative may be converted into avariety of compounds, for instance including more soluble derivativeslike hydroxylated derivatives, which are easy to be excreted. Hence,depending upon the metabolic pathway thus occurring, any of thesehydroxylated derivatives may be regarded as a metabolite of thecompounds of formula (I).

Prodrugs are any covalently bonded compounds, which release in vivo theactive parent drug according to formula (I).

N-Oxides are compounds of formula (I) wherein nitrogen and oxygen aretethered through a dative bond.

If a chiral center or another form of an isomeric center is present in acompound of the present invention, all forms of such isomer or isomers,including enantiomers and diastereomers, are intended to be coveredherein. Compounds containing a chiral center may be used as a racemicmixture, an enantiomerically enriched mixture, or the racemic mixturemay be separated using well-known techniques and an individualenantiomer may be used alone. In cases in which compounds haveunsaturated carbon-carbon double bonds, both the cis (Z) and trans (E)isomers are within the scope of this invention.

In cases wherein compounds may exist in tautomeric forms, such asketo-enol tautomers, each tautomeric form is contemplated as beingincluded within this invention whether existing in equilibrium orpredominantly in one form.

In addition to the above, as known to those skilled in the art, theunsubstituted nitrogen on the pyrazole ring of the compounds of formula(I) rapidly equilibrates in solution to form a mixture of tautomers, asdepicted below:

wherein R, A and Ar are as defined above.

Accordingly, in the present invention, where only one tautomer isindicated for the compounds of formula (I), the other tautomer (Ia) isalso within the scope of the present invention, unless specificallynoted otherwise.

In the present description, unless otherwise specified, with the term“straight or branched C₁-C₆ alkyl”, hence comprehensive of C₁-C₄ alkyl,we intend any of the groups such as, for instance, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl,n-hexyl, and the like.

With the term “C₃-C₆ cycloalkyl” we intend, unless otherwise provided,3- to 6-membered all-carbon monocyclic ring, which may contain one ormore double bonds but does not have a completely conjugated π-electronsystem. Examples of cycloalkyl groups, without limitation, arecyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexene and cyclohexadiene.

With the term “heterocyclyl” (also known as “heterocycloalkyl”) weintend a 3- to 7-membered, saturated or partially unsaturatedcarbocyclic ring where one or more carbon atoms are replaced byheteroatoms such as nitrogen, oxygen and sulfur. Not limiting examplesof heterocyclyl groups are, for instance, pyran, pyrrolidine, pyrroline,imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline,thiazolidine, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine,piperazine, morpholine and the like.

With the term “aryl” we intend carbocyclic or heterocyclic with from 1to 2 ring moieties, either fused or linked to each other by singlebonds, wherein at least one of the rings is aromatic; if present, anyaromatic heterocyclic ring also referred to as heteroaryl group,comprises a 5 to 6 membered ring with from 1 to 3 heteroatoms selectedamong N, NH, O or S. Examples of aryl groups according to the inventionare, for instance, phenyl, biphenyl, α- or β-naphthyl, dihydronaphthyl,thienyl, benzothienyl, furyl, benzofuranyl, pyrrolyl, imidazolyl,pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, purinyl,quinolyl, isoquinolyl, dihydroquinolinyl, quinoxalinyl, benzodioxolyl,indanyl, indenyl, triazolyl, and the like.

According to the present invention and unless otherwise provided, theabove R group may be optionally substituted, in any of their freepositions, by one or more groups, for instance 1 to 6 groups,independently selected from: halogen, nitro, oxo groups (═O), cyano,C₁-C₆ alkyl, polyfluorinated alkyl, polyfluorinated alkoxy, alkenyl,alkynyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, cycloalkyl,hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylenedioxy,alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy,heterocyclylcarbonyloxy, alkylideneaminooxy, carboxy, alkoxycarbonyl,aryloxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, amino,ureido, alkylamino, dialkylamino, arylamino, diarylamino,heterocyclyamino, formylamino, alkylcarbonylamino, arylcarbonylamino,heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl,alkoxycarbonylamino, hydroxyaminocarbonyl, alkoxyimino,alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino,formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl,heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,heterocyclylaminosulfonyl, arylthio, alkylthio phosphonate andalkylphosphonate. In their turn, whenever appropriate, each of the abovesubstituent may be further substituted by one or more of theaforementioned groups.

In this respect, with the term halogen atom we intend a fluorine,chlorine, bromine or iodine atom.

With the term alkenyl or alkynyl we intend any of the aforementionedstraight or branched C₂-C₆ alkyl groups further bearing a double ortriple bond. Non limiting examples of alkenyl or alkynyl groups of theinvention are, for instance, vinyl, allyl, 1-propenyl, isopropenyl,1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1-hexenyl, ethynyl,2-propynyl, 4-pentynyl, and the like.

With the term polyfluorinated alkyl or alkoxy we intend any of the abovestraight or branched C₁-C₆ alkyl or alkoxy groups which are substitutedby more than one fluorine atom such as, for instance, trifluoromethyl,trifluoroethyl, 1,1,1,3,3,3-hexafluoropropyl, trifluoromethoxy and thelike.

With the term alkoxy, aryloxy, heterocyclyloxy and derivatives thereofwe intend any of the above C₁-C₆ alkyl, aryl or heterocyclyl groupslinked to the rest of the molecule through a oxygen atom (—O—).

From all of the above, it is clear to the skilled person that any groupwhich name is a composite name such as, for instance, cycloalkylalkyl,arylalkyl, heterocyclylalkyl, alkoxy, alkylthio, aryloxy, arylalkyloxy,alkylcarbonyloxy and the like, have to be intended as conventionallyconstrued by the parts from which they derive. As an example, a groupsuch as heterocyclylalkyloxy is an alkoxy group, e.g. alkyloxy, whereinthe alkyl moiety is further substituted by a heterocyclyl group, andwherein C₁-C₆ alkyl and heterocyclyl are as above defined.

Pharmaceutically acceptable salts of the compounds of formula (I)include the acid addition salts with inorganic or organic acids, e.g.,nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric,acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic,malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic,methanesulphonic, isethionic and salicylic acid. Preferably, the acidaddition salt of the compounds of the invention is selected between thehydrochloride or mesylate salt.

Pharmaceutically acceptable salts of the compounds of formula (I) alsoinclude the salts with inorganic or organic bases, e.g., alkali oralkaline-earth metals, especially sodium, potassium, calcium ormagnesium hydroxides, carbonates or bicarbonates, acyclic or cyclicamines, preferably methylamine, ethylamine, diethylamine, triethylamine,piperidine and the like.

A preferred class of compounds of formula (I) are the compounds wherein:

R is a C₁-C₆ alkyl substituted by heterocyclyl or aryl, or an optionallyfurther substituted heterocyclyl or aryl.

Another preferred class of compounds of formula (I) are the compoundswherein:

R is heterocyclylmethyl, arylmethyl, or an optionally furthersubstituted heterocyclyl or aryl;

Ar is an optionally substituted phenyl, thienyl or furyl.

A further preferred class of compounds of formula (I) are the compoundswherein:

R is an optionally further substituted heterocyclyl or aryl.

A particularly preferred class of compounds of formula (I) are thecompounds wherein:

Ar is a group selected from:

wherein R_(1,) R′₁ and R″₁ are independently hydrogen, halogen, nitro,oxo groups (═O), cyano, C₁-C₆ alkyl, polyfluorinated alkyl,polyfluorinated alkoxy, hydroxyalkyl, hydroxy, alkoxy, alkylcarbonyloxy,carboxy, alkoxycarbonyl, aryloxycarbonyl, amino, ureido, alkylamino,dialkylamino, alkylcarbonylamino, heterocyclylcarbonylamino,alkylsulfonylamino, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl,alkylsulfonyl, aminosulfonyl, and alkylthio.

A most preferred class of compounds of formula (I) are compoundswherein:

Ar is a group of formula

wherein R₁ and R′₁ are as defined above.

Another most preferred class of compounds of formula (I) are compoundswherein:

R is a group selected from:

wherein R₂ is selected from: C₁-C₆ alkyl, halogen, nitro, oxo groups(═O), cyano, polyfluorinated alkyl, polyfluorinated alkoxy, alkenyl,alkynyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, cycloalkyl,hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylenedioxy,alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy,heterocyclylcarbonyloxy, alkylideneaminooxy, carboxy, alkoxycarbonyl,aryloxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, amino,ureido, alkylamino, dialkylamino, arylamino, diarylamino,heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino,heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl,alkoxycarbonylamino, hydroxyaminocarbonyl, alkoxyimino,alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino,formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl,heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,heterocyclylaminosulfonyl, arylthio, alkylthio phosphonate andalkylphosphonate.

Ar is a group of formula:

wherein R₁ and R′₁ are as defined above.

Specific compounds of the invention are listed below (for the meaning ofthe codes, see the Examples section):

N-(2,6-dichlorophenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxamide(A1-Z-B1);

N-[6,6-dimethyl-5-(phenylacetyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B2);

N-(2,6-difluorophenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxamide(A1-Z-B3);

N-{5-[(3,5-difluorophenyl)acetyl]-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B4);

N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B5);

N-(2,6-dichlorophenyl)-6,6-dimethyl-3-{[3-(4-methylpiperazin-1-yl)benzoyl]amino}-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxamide(A2-Z-B1);

N-{5-[(2,6-dichlorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B7);

N-{6,6-dimethyl-5-[(2-nitrophenyl)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B9);

N-{5-[(2-methoxyphenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B15);

N-{5-[(3-chlorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B19);

N-{5-[(3-methoxyphenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B20);

N-{5-[(3-bromophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B21);

N-{5-[(4-fluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B25);

N-{6,6-dimethyl-5-[(2-methylphenyl)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B27);

N-{5-[(3-fluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B28);

N-{6,6-dimethyl-5-[(3-methylphenyl)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B29);

N-{6,6-dimethyl-5-[(2,3,6-trifluorophenyl)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B33);

N-[5-(mesitylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B34);

N-{5-[(2,4-dichlorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B36);

N-{5-[(2-fluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B37);

N-{5-[(2-chloro-6-fluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B38);

N-(6,6-dimethyl-5-{[2-(trifluoromethyl)phenyl]acetyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B42);

N-(6,6-dimethyl-5-{[2-nitro-4-(trifluoromethyl)phenyl]acetyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B43);

N-{5-[(3,4-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B44);

N-{5-[(2,5-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B45);

N-{5-[(2,4-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B46);

N-{5-[(2-chlorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B52);

N-{5-[(2-iodophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B53);

N-{5-[(2,3-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B54);

N-{6,6-dimethyl-5-[(2,4,6-trimethoxyphenyl)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B55);

N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-3-(4-methylpiperazin-1-yl)benzamide(A2-Z-B5);

N-[6,6-dimethyl-5-(2-thienylacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B56);

4-({5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}carbamoyl)benzoicacid (A6-Z-B5);

N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[(4-methylbenzoyl)amino]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A8-Z-B1);

3-[(4-chlorobenzoyl)amino]-N-(2,6-dichlorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A11-Z-B1);

N-(2,6-dichlorophenyl)-3-[(3-fluorobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A16-Z-B1);

3-(benzoylamino)-N-(2,6-dichlorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A17-Z-B1);

N-(2,6-dichlorophenyl)-6,6-dimethyl-3-{[(2E)-3-phenylprop-2-enoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A19-Z-B1);

N-(2,6-dichlorophenyl)-3-[(4-methoxybenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A24-Z-B1);

N-(2,6-dichlorophenyl)-3-(2-furoylamino)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A26-Z-B1);

N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[(2-thienylcarbonyl)amino]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A30-Z-B1);

N-(2,6-dichlorophenyl)-3-[(2,4-difluorobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A31-Z-B1);

N-(2,6-dichlorophenyl)-3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A32-Z-B1);

N-(2,6-dichlorophenyl)-3-[(3,4-dimethoxybenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A33-Z-B1);

N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-2-fluorobenzamide(A47-Z-B5);N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(dimethylamino)benzamide(A65-Z-B5);

4-({5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}carbamoyl)benzoicacid (A6-Z-B1);

N-(2,5-dimethylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B59);

6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-N-[2-(trifluoromethoxy)phenyl]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B60);

N-(2,6-diisopropylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B73);

N-(2,6-dimethylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B74);

N-(2-methoxyphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B77);

N-(2-chlorophenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B78);

N-(2-isopropylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B80);

N-(2,6-diethylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B85);

N-(2-chloro-6-methylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B89);

N-(2-fluorophenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B92);

6,6-dimethyl-N-(2-methylphenyl)-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B94);

N-(2,6-dimethoxyphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B95);

N-(2-tert-butylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B96);

6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-N-[2-(methylthio)phenyl]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B102);

formicacid—N-[2-fluoro-6-(trifluoromethyl)phenyl]-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxamide(1:1) (A1-Z-B104);

N-(2-ethylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B106);

6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-N-[2-(trifluoromethyl)phenyl]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B108);

N-[2-chloro-6-(trifluoromethyl)phenyl]-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B111);

methyl3-({5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}carbamoyl)benzoate(A89-Z-B1);

N-(2,6-dichlorophenyl)-3-[(2,5-difluorobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A51-Z-B1);

N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[(3-methylbenzoyl)amino]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A52-Z-B1);

3-[(1-benzothien-2-ylcarbonyl)amino]-N-(2,6-dichlorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A55-Z-B1);

N-(2,6-dichlorophenyl)-3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A66-Z-B1);

3-{[(4-bromo-2-thienyl)carbonyl]amino}-N-(2,6-dichlorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A68-Z-B1);

N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-3-fluorobenzamide(A16-Z-B5);

N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}benzamide(A17-Z-B5);

N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-methoxybenzamide(A24-Z-B5);

N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-2-furamide(A26-Z-B5);

N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}thiophene-2-carboxamide(A30-Z-B5);

N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-N′-(1-methylpiperidin-4-yl)terephthalamide(A72-Z-B5);

N-{5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-N′-[3-(dimethylamino)propyl]terephthalamide(A71-Z-B1);

N-{5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-N′-(1-methylpiperidin-4-yl)terephthalamide(A72-Z-B1);

N-{5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}terephthalamide(A75-Z-B1);

N-{5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-N′-hydroxyterephthalamide(A76-Z-B1);

N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[(4-{[(1-methylpiperidin-4-yl)carbonyl]amino}benzoyl)amino]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A77-Z-B1);

N-(2,6-dichlorophenyl)-6,6-dimethyl-3-{[4-(methylsulfonyl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A78-Z-B1);

3-({5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}carbamoyl)benzoicacid (A79-Z-B1);

N-{5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}isophthalamide(A80-Z-B1);

N-{5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-N′-(1-methylpiperidin-4-yl)isophthalamide(A81-Z-B1);

N-{5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-N′-hydroxyisophthalamide(A82-Z-B1);

N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[(3-{[(1-methylpiperidin-4-yl)carbonyl]amino}benzoyl)amino]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A83-Z-B1);

3-[(3-aminobenzoyl)amino]-N-(2,6-dichlorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A84-Z-B1);

3-[(4-aminobenzoyl)amino]-N-(2,6-dichlorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A85-Z-B1);

N-(2,6-dichlorophenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)-3-nitrobenzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A86-Z-B1);

N-(2,6-dichlorophenyl)-3-[(4-fluoro-3-nitrobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A87-Z-B1);

diethyl[4-({5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}carbamoyl)phenyl]phosphonate(A91-Z-B1);

N-(3,5-dimethylisoxazol-4-yl)-6,6-dimethyl-3-({[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamidetrifluoroacetate (A1-Z-B115);

N-(2-cyanophenyl)-6,6-dimethyl-3-({[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamidetrifluoroacetate (A1-Z-B116);

N-(2-chloropyridin-3-yl)-6,6-dimethyl-3-({[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamidetrifluoroacetate (A1-Z-B120);

N-(2-bromo-6-fluorophenyl)-6,6-dimethyl-3-({[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamidetrifluoroacetate (A1-Z-B122);

N-(2,6-dichloro-4-nitrophenyl)-6,6-dimethyl-3-({[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamidetrifluoroacetate (A1-Z-B124);

N-[2,6-dichloro-4-(trifluoromethoxy)phenyl]-6,6-dimethyl-3-({[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamidetrifluoroacetate (A1-Z-B128);

N-(2,6-dichlorophenyl)-3-[({2-[(2-methoxyethyl)amino]-4-(4-methylpiperazin-1-yl)phenyl}carbonyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A95-Z-B1), and

N-(2,6-dichlorophenyl)-3-({[2-{[(1S)-2-methoxy-1-methylethyl]amino}-4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A96-Z-B1).

The present inventions also provides a process for the preparation ofcompounds of formula (I). Compounds of formula (I) and thepharmaceutically acceptable salts may be obtained by two independentways: pathway A or pathway B.

Pathway A comprises:

a) reacting any of the two regioisomeric forms of the compound offormula (II)

wherein Q is a suitable protecting group, preferably tert-butoxycarbonyl(t-boc), with a compound of formula (III)

R—CO—Y   (III)

wherein R is as defined above and Y is an halogen atom, so as to obtainthe compound of formula (IV)

wherein R and Q are defined as above;

b) deprotecting the amino group of the compound of formula (IV) so as toobtain the corresponding derivative of formula (V)

wherein R has the above reported meanings;

c) reacting the compound of formula (V) according to any one of thealternative steps c.1), c.2), c.3):

c1) with an acid of formula (VI),

Ar-A-COOH   (VI)

wherein Ar is as defined above and A is CH₂, in the presence of asuitable condensing agent so as to obtain a compound of formula (VII)

wherein R and Ar are as defined above and A is CH₂;

c.2) with an isocyanate of formula (VIII)

Ar—NCO   (VIII)

wherein Ar is as defined above, so as to obtain a compound of formula(VII) wherein R and Ar are as defined above and A is NH;

c.3) with an amine of formula (IX)

Ar—NH₂   (IX)

wherein Ar is as defined above, in the presence of triphosgene,di-tert-butyl dicarbonate or of a suitable chloroformate so as to obtaina compound of formula (VII) wherein R and Ar are as defined above and Ais NH;

d) reacting the compound of formula (VII) prepared according to any oneof steps from c.1) to c.3) under basic conditions, so as to obtain thecorresponding derivative of formula (I) defined above; and, optionally,

e) converting them into other compounds of formula (I) and/or intohydrates, solvates, complexes, metabolites, prodrugs, carriers, N-oxidesand pharmaceutically acceptable salts thereof.

Pathway B comprises:

f) removing the amino protecting group Q from compound of formula (II)as defined above, so to obtain a compound of formula (X);

g) reacting compound of formula (X) accordingly to any one of thealternative steps c.1), c.2) or c.3), to obtain a compound of formula(XI)

wherein Ar and A are defined above;

h) reacting compounds of formula (XI) as defined above, with compoundsof formula (III) as defined above, so to obtain compounds of formula(VII) as defined above;

i) reacting the resulting compound of formula (VII) under basicconditions, so as to obtain the corresponding derivative of formula (I)as defined above; and, optionally,

j) converting them into other compounds of formula (I), and/or intohydrates, solvates, complexes, metabolites, prodrugs, carriers, N-oxidesand pharmaceutically acceptable salts thereof.

It is to be noted that a compound of formula (II), (IV), (V), (VII), (X)and (XI) as defined above can be in any one of its isomeric forms a orb:

The two isomers of formula (a) and (b) may be conveniently separatedaccording to well-known methods, for instance under chromatographicconditions, and each isomer so isolated subsequently worked out. In thealternative, the mixture of isomers can be treated as such in thesubsequent steps of the process, without providing any separation. Infact, as the ethoxycarbonyl group leading to two distinct isomers isfinally removed at the end of the process, it is clear to the skilledperson that both the above pathways can be carried out for preparing thecompounds of formula (I) of the invention. Preferably, however, theprocess is carried out by first separating and isolating the two isomersof formula (a) and (b) from their mixture, as reported in the workingexamples, and by subsequently reacting them to the desired compounds.

The above process can be carried out according to methods well known inthe art.

From all of the above, it is clear to the person skilled in the art thatif a compound of formula (I), prepared according to the above process,is obtained as a mixture of isomers, their separation into the singleisomers of formula (I), carried out according to conventionaltechniques, is still within the scope of the present invention.

Likewise, the conversion into the free compound (I) of a correspondingsalt thereof, according to well-known methods, is still within the scopeof the invention.

According to step (a) or (h) of the process, the compound of formula(II) or (XI) is reacted with a suitable derivative of formula (III)wherein Y represents a halogen atom, preferably chlorine or bromine.Typically, the compound of formula (II) or (XI) is dissolved in asuitable solvent such as dichloromethane, dimethylformamide,tetrahydrofuran, dioxane or the like, and a suitable base such astriethylamine, diisopropylethylamine, sodium carbonate or the like isadded. The compound of formula (III) is then added and the mixturestirred for a time of about 2 to about 15 hours, at a temperatureranging from about 20° C. to about 80° C. A suitable catalyst such asdimethylaminopyridine may be optionally used.

According to step (b) or (f) of the process, the protected amino groupin formula (IV) or (II) is deprotected under well-known operativeconditions, for instance under acidic conditions in the presence oftrifluoroacetic or hydrochloric acid. The compound of formula (IV) or(II) is thus suspended in a suitable solvent such as dichloromethane ordioxane, and treated with a concentrated solution of the selected acid.Alternatively, commercially available solutions of gaseous hydrogenchloride dissolved in dioxane (4 M HCl) may be advantageously employed.The mixture is then stirred for a time of about 2 hours to about 15hours at a temperature ranging from about 20° C. to about 40° C.

According to step (c.1) of the process, the compound of formula (V) or(X) is reacted with an acid derivative of formula (VI). The condensationis carried out in the presence of a suitable condensing agent such as,for instance, dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC) or O-benzotriazolyltetramethylisouronium tetrafluoroborate (TBTU), and by operatingaccording to well-known methods for preparing carboxamido derivatives.

According to step (c.2) of the process, the compound of formula (V) or(X) is reacted with an isocyanate of formula (VIII). The reaction iscarried out in tetrahydrofuran (THF) or in a suitable halogenatedhydrocarbon, preferably dichloromethane (DCM), for a time of about 2hours to about 15 hours at a temperature ranging from about −0° C. to40° C.

According to step (c.3) of the process, the compound of formula (V) or(X) is reacted with an amine of formula (IX) in the presence oftriphosgene, di-tert-butyl dicarbonate or of a suitable chloroformate,for instance 4-nitrophenyl chloroformate, so as to get the correspondingureido derivative. The reaction is carried out in tetrahydrofuran (THF)or in a suitable halogenated hydrocarbon, preferably dichloromethane(DCM), and in the presence of a suitable amine such asdiisopropylethylamine or triethylamine at a temperature ranging from −20to 150° C. irradiating if necessary the reaction with microwave.

According to step (d) or (i) of the process, the compound of formula(VII) being obtained in any one of steps from (c.1) to (c.3) is reactedwith a suitable base, for instance triethylamine, piperidine,N-methylpiperazine or NaOH, and in the presence of a suitable solventsuch as methanol or ethanol so as to obtain the desired compound offormula (I). The reaction is carried out at a temperature ranging fromabout 20° C. to 70° C.

Finally, according to steps (e) or (j) of the process, these lattercompounds (I) may be optionally converted into hydrates, solvates,complexes, metabolites, prodrugs, carriers, N-oxides andpharmaceutically acceptable salts thereof by working according toconventional methods or, alternatively, may be converted into additionalcompounds of formula (I). Just as a non limiting example, compounds offormula (I) bearing a carboxyester function may be converted into avariety of derivatives according to methods well known in the art toconvert carboxyester groups into carboxamides, N-substitutedcarboxamides, N,N-disubstituted carboxamides, carboxylic acids, and thelike.

The operative conditions are those widely known in the art and maycomprise, for instance in the conversion of a carboxyester group into acarboxamide group, the reaction with ammonia or ammonium hydroxide inthe presence of a suitable solvent such as a lower alcohol,dimethylformamide or mixtures thereof, preferably the reaction iscarried out with ammonium hydroxide in a methanol/dimethylformamidemixture, at a temperature ranging from about 50° C. to about 100° C.Analogous operative conditions apply in the preparation of N-substitutedor N,N-disubstituted carboxamides wherein a suitable primary orsecondary amine is used in place of ammonia or ammonium hydroxide.Likewise, carboxyester groups may be converted into carboxylic acidderivatives through basic or acidic hydrolysis conditions, widely knownin the art and then coupled with a suitable primary or secondary aminesin presence of a condensing agent to yield the corresponding carboxamidoderivatives. As an additional example, compounds of formula (I) bearingan amino function may be easily converted into the correspondingcarboxamido or ureido derivatives by reaction with suitable acylcloridesor with suitable acids in presence of a condensing agent or in the caseof ureido derivatives with suitable amines and triphosgene as describedabove in the step (c.3).

From all of the above it is clear to the skilled person that accordingto step (e) or (j) of the process, any compound of formula (I) bearing afunctional group which can be further derivatized to another functionalgroup, by working according to methods well known in the art thusleading to other compounds of formula (I), has to be intended ascomprised within the scope of the present invention.

According to any variant of the process for preparing the compounds offormula (I), the starting materials and any other reactants are known oreasily prepared according to known methods.

The starting material of formula (II) can be prepared as described inthe aforementioned WO04/56827.

The starting material of formula (III) are commercially available or canbe prepared as described in WO07/68619 (Nerviano Medical Sciences Srl).

The starting materials of formula (VI), (VIII) and (IX) are commerciallyavailable.

As it will be readily appreciated, if the compounds of formula (I)prepared according to the process described above are obtained as anadmixture of isomers, their separation into the single isomers offormula (I), according to conventional techniques, is within the scopeof the present invention. Conventional techniques for racemateresolution include, for instance, partitioned crystallization ofdiastereoisomeric salt derivatives or preparative chiral HPLC.

In addition, it is clear from the above that a given compound of formula(I) may be prepared either by starting from the mixture of theregioisomers of formula (II) or, alternatively, from each one of the tworegioisomers themselves.

When preparing the compounds of formula (I) according to any one of theaforementioned process variants, optional functional groups within thestarting materials or the intermediates thereof and which could giverise to unwanted side reactions, need to be properly protected accordingto conventional techniques. Likewise, the conversion of these latterinto the free deprotected compounds may be carried out according toknown procedures.

Pharmacology

The compounds of formula (I) are active as protein kinase inhibitors andare therefore useful, for instance, to restrict the unregulatedproliferation of tumor cells.

In therapy, they may be used in the treatment of various tumors, such asthose formerly reported, as well as in the treatment of other cellproliferative disorders such as psoriasis, vascular smooth cellproliferation associated with atherosclerosis and post-surgical stenosisand restenosis.

The inhibiting activity of putative PLK-1 inhibitors and the potency ofselected compounds was determined through the assay described below.

The short forms and abbreviations used herein have the followingmeaning:

Ci Curie

DMSO dimethylsulfoxide

KDa kiloDalton

microCi microCurie

mg milligram

microg microgram

ng nanogram

L liter

mL milliliter

microL microliter

M molar

mM millimolar

microM micromolar

nM nanomolar

Et Ethyl

Cloning, Expression and Purification of Recombinant PLK1 Kinase Domain.

PLK1 kinase domain (corresponding to residues 2-345 of the full lengthsequence, see Swiss-Prot accession number P53350) was PCR amplified fromthe full-length human PLK1 gene purchased from imaGenes as cloneIRATp970A078D.

Amplification was performed using the forward oligonucleotide:

5′GGGGACAAGTTTGTACAAAAAAGCAGGCTTATTC [SEQ ID NO: 1]GAAAACCTGTATTTTCAGGGCCCTAGTGCTGCAGTG ACTGCAGGGAAG3′

and the reverse oligonucleotide:

5′GGGGACCACTTTGTACAAGAAAGCTGGGTTTCAC [SEQ ID NO: 2]TATTTATTGAGGACTGTGAGGGGCTT-3′.

For cloning purposes, the oligonucleotides included attB sites in orderto obtain an attB-flanked PCR product suitable for cloning using theGateway® technology (Invitrogen). Furthermore, for purificationpurposes, forward primer included a TEV® cleavage site (AmershamBiosciences). The resulting PCR product was cloned in the pDONR221plasmid and then transferred in the baculovirus expression vectorpVL1393 (Invitrogen) Gateway®-modified. For expression and purificationpurposes, a His tag was added N-terminal to the PLK kinase domain.Cloning was performed according to the protocols described in theGateway® manual.

Baculoviruses were generated by cotransfecting Sf9 insect cells with theexpression vector and the viral DNA using the BaculoGold® transfectionkit (Pharmingen). Viral supernatant was recovered after 5 days andsubjected to 3 rounds of amplification to increase viral titer.Recombinant protein was produced by infecting High5 insect cells. After48 hours of infection, cells were recovered, pelletted and freezed at−80° C. For purification of recombinant protein, pellet was thawed,resuspended in lysis buffer (PBS, NaCl 150 mM, CHAPS 0.1%, DTT 20 mM,glycerol 10%, protease inhibitors) and lysed by sonication. Lysate wascleared by centrifugation and loaded on a Nichel affinity column. Afterextensive wash, recombinant protein was cleaved and eluted by incubationwith TEV® protease.

Biochemical Assay for Inhibitors of PLK-1 Kinase Activity

The inhibitory activity of putative kinase inhibitors and the potency ofselected compounds were determined using a trans-phosphorylation assay.

Specific peptide or protein substrates are trans-phosphorylated by theirspecific serine-threonine or tyrosine kinase, in the presence of ATPtraced with ³³P-γ-ATP, and in the presence of their own optimal bufferand cofactors.

At the end of the phosphorylation reaction, more than 98% cold ATP andradioactive ATP is captured by an excess of the ion exchange dowexresin; the resin then settles down to the bottom of the reaction plateby gravity.

Supernatant, containing the phosphorylated substrate, is subsequentlywithdrawn and transferred into a counting plate, then evaluated byβ-counting.

Reagents/Assay Conditions

i. Dowex Resin Preparation

500 g of wet resin (SIGMA, custom prepared resin DOWEX 1×8 200-400 mesh,2.5 Kg) are weighed out and diluted to 2 L in 150 mM sodium formate, pH3.00.

The resin is allowed to settle down (some hours) and then thesupernatant is discarded.

After three washes as above over a couple of days, the resin is allowedto settle, the supernatant is discarded and two volumes of 150 mM sodiumformate buffer are added per volume of pellet. The pH is then measuredand should be around 3.00. The washed resin is stable for more than oneweek; the stock resin is kept at 4° C. before use.

ii. Kinase Buffer (KB)

Kinase buffer was composed of 50 mM HEPES pH 7.9 containing 10 mM MnCl₂,1 mM DTT, 3 microM NaVO₃, and 0.2 mg/mL BSA, 10 mM β-glycerophosphate.

iii Assay Conditions

The kinase assay was run with a final enzyme concentration PLK-1 of 3nM, in presence of 40 microM ATP, 3 nM ³³P-γ-ATP and 85 microM substratealpha-casein, SIGMA, #C-3240.

Robotized Dowex Assay

1) 3× Enzyme mix (done in Kinase Buffer 3×), 5 microL/well

2) 3× substrate and ATP mix (done in ddH2O), together with ³³P-γ-ATP, 5microL/well

3) 3× test compounds (diluted into ddH2O—3% DMSO)—5 microL/well

Compound Dilution and Assay Scheme is Reported Below.

i. Dilution of Compounds

10 mM stock solutions of test compounds in 100% DMSO were distributedinto 96 well 12×8 format microtiter plates.

For % inhibition studies, individual dilution plates at 1 mM, 100 microMand 10 microM are prepared in 100% DMSO, then diluted at a 3×concentration (30, 3 and 0.3 microM) in ddH₂O, 3% DMSO. A Multimek 96(Beckman) is used for dilutions and compound pipetting into the testplates

For IC50 determination, compounds are received as 1 mM, 100% DMSOsolutions, plated into the first column of a microtiter plate (A1 toG1), 100 microL.

A Biomek 2000 (Beckman) is used for serial 1:3 dilutions in water, 3%DMSO, from column A1 to A10 and for all the seven compounds in theplate. In a standard experiment, the highest concentration of allcompounds is 30 microM, then diluted in the final test mixture down to10 microM.

ii. Assay Scheme

384-well plates, V bottom (test plates) are prepared with 5 microL ofthe compound dilution (3×) and then placed onto a PlateTrak 12 robotizedstation (Perkin Elmer; the robot has one 384-tips pipetting head forstarting the assay plus one 96-tips head for dispensing the resin)together with one reservoir for the Enzyme mix (3×) and one for the ATPmix (3×). At the start of the run, the robot aspirates 5 microL of ATPmix, makes an air gap inside the tips (3 microL) and aspirates 5 microLof PLK1 mix. The following dispensation into the plates allows thekinase reaction to start upon 3 cycles of mixing, done by the robotitself.

At this point, the correct concentration is restored for all reagents.

The robot incubates the plates for 60 minutes at room temperature, andthen stops the reaction by pipetting 70 microL of dowex resin suspensioninto the reaction mix. Three cycles of mixing are done immediately afterthe addition of the resin.

Another mixing cycle is performed after all the plates are stopped, thistime using normal tips: the plates are then allowed to rest for aboutone hour in order to maximize ATP capture. At this point, 20 microL ofthe supernatant are transferred into 384-Optiplates (Perkin-Elmer), with70 microL of Microscint 40 (Perkin-Elmer); after 5 min of orbitalshaking the plates are read on a Perkin-Elmer Top Count radioactivitycounter.

iii. Data Analysis

Data are analyzed by an internally customized version of the SW package“Assay Explorer” that provides either % inhibition for primary assays orsigmoidal fittings of the ten-dilutions curves for IC50 determination,for the secondary assays/hit confirmation routines.

Biochemical Assay for Inhibitors of Aurora-2 Kinase Activity

The in vitro kinase inhibition assay was conducted in the same way asdescribed for PLK-1 enzyme.

i. Kinase Buffer (KB) for Aurora-2

The kinase buffer was composed of 50 mM HEPES, pH 7.0, 10 mM MnCl₂, 1 mMDTT, 3 microM NaVO₃, and 0.2 mg/mL BSA.

ii. Assay Conditions for Aurora-2 (Final Concentrations)

The kinase assay was run with an enzyme concentration of 2.5 nM, 10microM ATP, 1 nM ³³P-γ-ATP, and 8 microM substrate, composed of 4LRRWSLG repeats.

Inhibition Assay of Cdk2/Cyclin A Activity

Kinase reaction: 1.5 microM histone H1 substrate, 25 microM ATP (0.2microCi P33γ-ATP), 30 ng of baculovirus co-expressed Cdk2/Cyclin A, 10microM inhibitor in a final volume of 100 microL buffer (TRIS HCl 10 mMpH 7.5, MgCl₂ 10 mM, 7.5 mM DTT) were added to each well of a 96 Ubottom well plate. After 10 min at 37° C. incubation, reaction wasstopped by 20 microL EDTA 120 mM.

Capture: 100 microL were transferred from each well to MultiScreenplate, to allow substrate binding to phosphocellulose filter. Plateswere then washed 3 times with 150 microL/well PBS Ca⁺⁺/Mg⁺⁺ free andfiltered by MultiScreen filtration system.

In Vitro Cell Proliferation Assay

A2780 human ovarian and MCF7 human breast cancer cells (1250 cells/well)were seeded in white 384 well-plates in complete medium (RPMI1640 orEMEM plus 10% Fetal bovine serum) and treated with compounds dissolvedin 0.1% DMSO, 24 h after seeding. The cells were incubated at 37° C. and5% CO2 and after 72 hours the plates were processed using CellTiter-Gloassay (Promega) following the manufacturer's instruction.

CellTiter-Glo is a homogenous method based on the quantification of theATP present, an indicator of metabolitically active cells. ATP isquantified using a system based on luciferase and D-luciferin resultinginto light generation. The luminescent signal is proportional to thenumber of cells present in culture.

Briefly 25 microL/well reagent solution are added to each wells andafter 5 minutes shacking microplates are red by a luminometer. Theluminescent signal is proportional to the number of cells present inculture.

Given the above inhibition assays, the compounds of formula (I) of theinvention resulted to possess a remarkable PLK inhibitory activity,typically with IC₅₀ lower than 0.6 microM. See, as an example, thefollowing Table A reporting the experimental data of some representativecompounds of the invention of formula (I) being tested in biochemicalassay as PLK-1 inhibitors and in A2780 cell proliferation assay (IC₅₀microM) in comparison with the closest compound of the prior art,described in the aforementioned WO 02/12242, page 75, compound 1126.

TABLE A PLK-1 IC₅₀ A2780 IC₅₀ (microM) (microM) Cell proliferation CompdN^(o) Code Biochemical Assay Assay Reference — >4.2 2.66 Compound  44A1-Z-B42 0.075 0.38  60 A1-Z-B56 0.052 0.071 178 A1-Z-B106 0.096 0.019250 A84-Z-B1 0.030 0.119 251 A85-Z-B1 0.024 0.063  64 A8-Z-B1 0.2300.209

Surprisingly, the PLK-1 inhibitory activity of the compounds of thepresent invention resulted to be markedly superior to that of thereference compound.

So far, the novel compounds of the invention are unexpectedly endowedwith a PLK-1 inhibitory activity significantly higher than that of thestructurally closest prior art compounds of the aforementioned WO02/12242 and are thus particularly advantageous, in therapy, againstproliferative disorders associated with an altered cell cycle dependentkinase activity such as cancer.

The compounds of the present invention can be administered either assingle agents or, alternatively, in combination with known anticancertreatments such as radiation therapy or chemotherapy regimen incombination with cytostatic or cytotoxic agents, antibiotic-type agents,alkylating agents, antimetabolite agents, hormonal agents, immunologicalagents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2inhibitors), matrixmetalloprotease inhibitors, telomerase inhibitors,tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HERagents, anti-EGFR agents, anti-angiogenesis agents (e.g. angiogenesisinhibitors), farnesyl transferase inhibitors, ras-raf signaltransduction pathway inhibitors, cell cycle inhibitors, other cdksinhibitors, tubulin binding agents, topoisomerase I inhibitors,topoisomerase II inhibitors, and the like.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent within the approved dosagerange.

Compounds of formula (I) may be used sequentially with known anticanceragents when a combination formulation is inappropriate.

The compounds of formula (I) of the present invention, suitable foradministration to a mammal, e.g., to humans, can be administered by theusual routes and the dosage level depends upon the age, weight,conditions of the patient and administration route. For example, asuitable dosage adopted for oral administration of a compound of formula(I) may range from about 10 to about 500 mg per dose, from 1 to 5 timesdaily. The compounds of the invention can be administered in a varietyof dosage forms, e.g., orally, in the form tablets, capsules, sugar orfilm coated tablets, liquid solutions or suspensions; rectally in theform suppositories; parenterally, e.g., intramuscularly, or throughintravenous and/or intrathecal and/or intraspinal injection or infusion.

The present invention also includes pharmaceutical compositionscomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof in association with a pharmaceutically acceptableexcipient, which may be a carrier or a diluent.

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a suitable pharmaceutical form. For example, the solidoral forms may contain, together with the active compound, diluents,e.g., lactose, dextrose saccharose, sucrose, cellulose, corn starch orpotato starch; lubricants, e.g., silica, talc, stearic acid, magnesiumor calcium stearate, and/or polyethylene glycols; binding agents, e.g.,starches, arabic gum, gelatine methylcellulose, carboxymethylcelluloseor polyvinyl pyrrolidone; disintegrating agents, e.g., starch, alginicacid, alginates or sodium starch glycolate; effervescing mixtures;dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates,laurylsulphates; and, in general, non-toxic and pharmacologicallyinactive substances used in pharmaceutical formulations. Thesepharmaceutical preparations may be manufactured in known manner, forexample, by means of mixing, granulating, tabletting, sugar-coating, orfilm-coating processes.

The liquid dispersions for oral administration may be, e.g., syrups,emulsions and suspensions. As an example, the syrups may contain, ascarrier, saccharose or saccharose with glycerine and/or mannitol andsorbitol.

The suspensions and the emulsions may contain, as examples of carriers,natural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol. The suspension orsolutions for intramuscular injections may contain, together with theactive compound, a pharmaceutically acceptable carrier, e.g., sterilewater, olive oil, ethyl oleate, glycols, e.g., propylene glycol and, ifdesired, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injections or infusions may contain, as acarrier, sterile water or preferably they may be in the form of sterile,aqueous, isotonic, saline solutions or they may contain propylene glycolas a carrier.

The suppositories may contain, together with the active compound, apharmaceutically acceptable carrier, e.g., cocoa butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

With the aim of better illustrating the present invention, withoutposing any limitation to it, the following examples are now given.

Examples

Before describing the synthetic preparation of some compounds of formula(I) of the invention, as reported in the following examples, attentionshould be given to the fact that all the compounds are conveniently andunambiguously identified through a coding system (see following tableIII), some of them are herewith listed and indicated according to theirchemical name whilst others have been listed with the coding systemtogether with their ¹H-NMR data and/or HPLC/Mass data (see followingtable IV).

Each code, in particular, identifies a single specific final compound offormula (I) and consists of three units A-Z-B.

Each specific A and B group is represented and consecutively numbered inthe following table I and II respectively.

Z refers to the central core of the divalent moiety which is substitutedby groups A and B:

For ease of reference, all of the A and B groups of tables I and II havebeen identified with the proper chemical formula also indicating theirrespective point of attachment to the rest of the molecule Z.

Therefore, just as an example, the code A1-Z-B4 of table III representsthe compound of formula (I) having the central Z core substituted by thegroup A1 and by the group B4, so identifying the structure reportedbelow:

TABLE I A Code

A1 

A2 

A3 

A4 

A5 

A6 

A7 

A8 

A9 

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

A26

A27

A28

A29

A30

A31

A32

A33

A34

A35

A36

A37

A38

A39

A40

A41

A42

A43

A44

A45

A46

A47

A48

A49

A50

A51

A52

A53

A54

A55

A56

A57

A58

A59

A60

A61

A62

A63

A64

A65

A66

A67

A68

A69

A70

A71

A72

A73

A74

A75

A76

A77

A78

A79

A80

A81

A82

A83

A84

A85

A86

A87

A88

A89

A90

A91

A92

A93

TABLE II B Code

B1 

B2 

B3 

B4 

B5 

B6 

B7 

B8 

B9 

B10 

B11 

B12 

B13 

B14 

B15 

B16 

B17 

B18 

B19 

B20 

B21 

B22 

B23 

B24 

B25 

B26 

B27 

B28 

B29 

B30 

B31 

B32 

B33 

B34 

B35 

B36 

B37 

B38 

B39 

B40 

B41 

B42 

B43 

B44 

B45 

B46 

B47 

B48 

B49 

B50 

B51 

B52 

B53 

B54 

B55 

B56 

B57 

B58 

B59 

B60 

B61 

B62 

B63 

B64 

B65 

B66 

B67 

B68 

B69 

B70 

B71 

B72 

B73 

B74 

B75 

B76 

B77 

B78 

B79 

B80 

B81 

B82 

B83 

B84 

B85 

B86 

B87 

B88 

B89 

B90 

B91 

B92 

B93 

B94 

B95 

B96 

B97 

B98 

B99 

B100

B101

B102

B103

B104

B105

B106

B107

B108

B109

B110

B111

B112

B113

B114

B115

B116

B117

B118

B119

B120

B121

B122

B123

B124

B125

B126

B127

B128

As said above the following Table III shows all the compoundsconveniently and unambiguously identified through a coding system.

TABLE III N^(o) CODE 1 A1-Z-B1 2 A1-Z-B2 3 A1-Z-B3 4 A1-Z-B4 5 A1-Z-B5 6A2-Z-B1 7 A3-Z-B1 8 A1-Z-B6 9 A1-Z-B7 10 A1-Z-B8 11 A1-Z-B9 12 A1-Z-B1013 A1-Z-B11 14 A1-Z-B12 15 A1-Z-B13 16 A1-Z-B14 17 A1-Z-B15 18 A1-Z-B1619 A1-Z-B17 20 A1-Z-B18 21 A1-Z-B19 22 A1-Z-B20 23 A1-Z-B21 24 A1-Z-B2225 A1-Z-B23 26 A1-Z-B24 27 A1-Z-B25 28 A1-Z-B26 29 A1-Z-B27 30 A1-Z-B2831 A1-Z-B29 32 A1-Z-B30 33 A1-Z-B31 34 A1-Z-B32 35 A1-Z-B33 36 A1-Z-B3437 A1-Z-B35 38 A1-Z-B36 39 A1-Z-B37 40 A1-Z-B38 41 A1-Z-B39 42 A1-Z-B4043 A1-Z-B41 44 A1-Z-B42 45 A1-Z-B43 46 A1-Z-B44 47 A1-Z-B45 48 A1-Z-B4649 A1-Z-B47 50 A1-Z-B48 51 A1-Z-B49 52 A1-Z-B50 53 A1-Z-B51 54 A1-Z-B5255 A1-Z-B53 56 A1-Z-B54 57 A1-Z-B55 58 A4-Z-B1 59 A2-Z-B5 60 A1-Z-B56 61A5-Z-B5 62 A6-Z-B5 63 A7-Z-B1 64 A8-Z-B1 65 A9-Z-B1 66 A10-Z-B1 67A11-Z-B1 68 A12-Z-B1 69 A13-Z-B1 70 A14-Z-B1 71 A15-Z-B1 72 A16-Z-B1 73A17-Z-B1 74 A18-Z-B1 75 A19-Z-B1 76 A20-Z-B1 77 A21-Z-B1 78 A22-Z-B1 79A23-Z-B1 80 A24-Z-B1 81 A25-Z-B1 82 A26-Z-B1 83 A27-Z-B1 84 A28-Z-B1 85A29-Z-B1 86 A30-Z-B1 87 A31-Z-B1 88 A32-Z-B1 89 A33-Z-B1 90 A34-Z-B1 91A35-Z-B1 92 A36-Z-B1 93 A36-Z-B5 94 A37-Z-B5 95 A38-Z-B5 96 A39-Z-B5 97A40-Z-B5 98 A41-Z-B5 99 A42-Z-B5 100 A43-Z-B5 101 A44-Z-B5 102 A45-Z-B5103 A46-Z-B5 104 A47-Z-B5 105 A48-Z-B5 106 A4-Z-B5 107 A49-Z-B5 108A50-Z-B5 109 A51-Z-B5 110 A52-Z-B5 111 A53-Z-B5 112 A54-Z-B5 113A55-Z-B5 114 A56-Z-B5 115 A57-Z-B5 116 A58-Z-B5 117 A59-Z-B5 118A60-Z-B5 119 A61-Z-B5 120 A62-Z-B5 121 A63-Z-B5 122 A64-Z-B5 123A65-Z-B5 124 A66-Z-B5 125 A67-Z-B5 126 A68-Z-B5 127 A6-Z-B1 128 A69-Z-B5129 A1-Z-B57 130 A1-Z-B58 131 A1-Z-B59 132 A1-Z-B60 133 A1-Z-B61 134A1-Z-B62 135 A1-Z-B63 136 A1-Z-B64 137 A1-Z-B65 138 A1-Z-B66 139A1-Z-B67 140 A1-Z-B68 141 A1-Z-B69 142 A1-Z-B70 143 A1-Z-B71 144A1-Z-B72 145 A1-Z-B73 146 A1-Z-B74 147 A1-Z-B75 148 A1-Z-B76 149A1-Z-B77 150 A1-Z-B78 151 A1-Z-B79 152 A1-Z-B80 153 A1-Z-B81 154A1-Z-B82 155 A1-Z-B83 156 A1-Z-B84 157 A1-Z-B85 158 A1-Z-B86 159A1-Z-B87 160 A1-Z-B88 161 A1-Z-B89 162 A1-Z-B90 163 A1-Z-B91 164A1-Z-B92 165 A1-Z-B93 166 A1-Z-B94 167 A1-Z-B95 168 A1-Z-B96 169A1-Z-B97 170 A1-Z-B98 171 A1-Z-B99 172 A1-Z-B100 173 A1-Z-B101 174A1-Z-B102 175 A1-Z-B103 176 A1-Z-B104 177 A1-Z-B105 178 A1-Z-B106 179A1-Z-B107 180 A1-Z-B108 181 A1-Z-B109 182 A1-Z-B110 183 A1-Z-B111 184A1-Z-B112 185 A89-Z-B1 186 A90-Z-B1 187 A51-Z-B1 188 A52-Z-B1 189A53-Z-B1 190 A55-Z-B1 191 A56-Z-B1 192 A57-Z-B1 193 A58-Z-B1 194A59-Z-B1 195 A60-Z-B1 196 A61-Z-B1 197 A62-Z-B1 198 A63-Z-B1 199A64-Z-B1 200 A66-Z-B1 201 A67-Z-B1 202 A68-Z-B1 203 A7-Z-B5 204 A8-Z-B5205 A9-Z-B5 206 A10-Z-B5 207 A11-Z-B5 208 A12-Z-B5 209 A13-Z-B5 210A14-Z-B5 211 A15-Z-B5 212 A16-Z-B5 213 A70-Z-B5 214 A17-Z-B5 215A18-Z-B5 216 A19-Z-B5 217 A20-Z-B5 218 A21-Z-B5 219 A22-Z-B5 220A23-Z-B5 221 A24-Z-B5 222 A25-Z-B5 223 A26-Z-B5 224 A27-Z-B5 225A28-Z-B5 226 A29-Z-B5 227 A30-Z-B5 228 A31-Z-B5 229 A32-Z-B5 230A33-Z-B5 231 A34-Z-B5 232 A35-Z-B5 233 A71-Z-B5 234 A72-Z-B5 235A71-Z-B1 236 A17-Z-B6 237 A17-Z-B2 238 A72-Z-B1 239 A73-Z-B1 240A96-Z-B1 241 A75-Z-B1 242 A76-Z-B1 243 A77-Z-B1 244 A78-Z-B1 245A79-Z-B1 246 A80-Z-B1 247 A81-Z-B1 248 A82-Z-B1 249 A83-Z-B1 250A84-Z-B1 251 A85-Z-B1 252 A86-Z-B1 253 A87-Z-B1 254 A88-Z-B1 255A91-Z-B1 256 A74-Z-B1 257 A92-Z-B1 258 A93-Z-B1 259 A1-Z-B113 260A1-Z-B114 261 A1-Z-B115 262 A1-Z-B116 263 A1-Z-B117 264 A1-Z-B118 265A1-Z-B119 266 A1-Z-B120 267 A1-Z-B121 268 A1-Z-B122 269 A1-Z-B123 270A1-Z-B124 271 A1-Z-B125 272 A1-Z-B126 273 A1-Z-B127 274 A1-Z-B128 275A94-Z-B1 276 A95-Z-B1

Example 16,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylicAcid 5-tert-butyl ester 2-ethyl ester Formula (IV),R=4-(4-methyl-piperazin)-phenyl

To a solution of3-Amino-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid5-tert-butyl ester 2-ethyl ester (2.50 g, 7.70 mmol) prepared asreported in WO2004/056827, N,N-diisopropylethylamine (14.6 ml, 33.6mmol) in anhydrous Dioxane (100 ml), 4-(4-Methyl-piperazin-1-yl)-benzoylchloride (0.24 g, 1.00 mmol) was added. The reaction was heated toreflux and stirred for 6 h. The solvent was removed under vacuum, theresidue dissolved in CH₂Cl₂ (150 mL) and washed with brine (1×100 mL).The organic phase was dried over sodium sulphate, the solvent evaporatedin vacuo and the residue purified by flash chromatography (Acetone/DCM80/20) affording 2.10 g (yield 52%) of the title compound.

ESI MS: m/z 527 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ 10.69 (s, 1H), 7.76 (m, 2H), 7.09 (m, 2H),4.55 (d, 2H, J=9.8 Hz), 4.48 (q, 2H, J=7.1 Hz), 3.34 (m, 4H), 2.52 (m,4H), 2.27 (s, 3H), 1.64 (s, 3H), 1.62 (s, 3H), 1.47 (s, 9H),1.38 (t, 3H,J=7.1 Hz).

By working in an analogous manner the following compounds were prepared:

3-[2-[(2-Methoxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzoylamino]-6,6-dimethyl-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylicAcid 5-tert-butyl ester 1-ethyl ester Formula (IV),R=2-[(2-Methoxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin)-phenyl,Q=carboxyethyl

ESI MS: m/z 696 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (t, J=7.07 Hz, 3H) 1.42-1.45 (m,9H) 1.71-1.78 (m, 6H) 2.23 (s, 3H) 2.41-2.48 (m, 4H) 3.16 (s, 3H)3.28-3.35 (m, 4H) 3.37-3.54 (m, 4H) 4.28-4.38 (m, 2H) 4.43 (q, J=6.99Hz, 2H) 6.92-6.94 (m, 1H) 6.98-7.04 (m, 1H) 7.77 (dd, J=8.90, 3.90 Hz,1H) 11.21 (s, 1H)

6,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylicAcid 5-tert-butyl ester 1-ethyl ester Formula (IV),R=2-nitro-4-(4-methyl-piperazin)-phenyl, Q=carboxyethyl

ESI MS: m/z 696 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (t, J=7.13 Hz, 3H) 1.44 (s, 9H)1.77 (s, 6H) 2.24 (s, 3H) 2.42-2.48 (m, 4H) 3.34-3.39 (m, 4H) 4.40 (d,J=8.66 Hz, 2H) 4.42-4.47 (m, 2H) 7.22 (dd, J=8.90, 2.19 Hz, 1H)7.41-7.43 (m, 1H) 7.60 (d, J=8.78 Hz, 1H) 11.57 (s, 1H).

3-[2-[((S)-2-Methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzoylamino]-6,6-dimethyl-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylicAcid 5-tert-butyl ester 1-ethyl ester Formula (IV),R=2-[((S)-2-Methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin)-phenyl,Q=carboxyethyl

ESI MS: m/z 710 (MH⁺);

Example 26,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicAcid ethyl ester dihydrochloride Formula (V),R=4-(4-methyl-piperazin)-phenyl

A suspension of6,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylicacid 5-tert-butyl ester 2-ethyl ester (1.5 g, 2.84 mmol) in 5M HCl indioxane (20 mL) was stirred at room temperature for 6 h, the solvent wasremoved in vacuo and the residue treated with ether (30 mL). Thesuspension was stirred for 30′ then the organic solvent was allowed byfiltration yielding 1.27 g (yield 90%) of the title compound as whitesolid

ESI MS: m/z 427 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ 11.39 (s, 1H), 10.68 (bs, 1H), 10.22 (bs,2H), 8.00 (m, 2H), 7.10 (m, 2H), 4.51 (m, 2H), 4.46 (q, 2H, J=7.1 Hz),3.42-3.35 (m, 8H), 2.84 (m, 3H), 1.80 (s, 6H), 1.37 (t, 3H, J=7.1 Hz).

By working in an analogous manner the following compounds were prepared:

3-Amino-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicAcid ethyl ester dihydrochloride Formula (X)

ESI MS: m/z 225 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ 9.75 (s, 3H), 6.77 (bs, 2H), 4.38 (q, 2H,J=7.1 Hz), 4.12 (t, 2H, J=5.0 Hz), 1.60 (s, 6H), 1.33 (t, 3H, J=7.1 Hz).6,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylicacid ethyl ester dihydrochloride

Formula (V), R=2-nitro-4-(4-methyl-piperazin)-phenyl

ESI MS: m/z 472(MH⁺);

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (t, J=7.13 Hz, 3H) 1.79 (s, 6H)2.83 (d, J=4.27 Hz, 3H) 3.07-3.19 (m, 2H) 3.29 (t, J=12.56 Hz, 2H)3.45-3.55 (m, 2H) 4.12 (d, J=13.78 Hz, 2H) 4.41-4.43 (m, 2H) 4.45 (q,J=7.07 Hz, 1H) 7.31 (dd, J=8.90, 2.56 Hz, 1H) 7.55 (d, J=2.56 Hz, 1H)7.70 (d, J=8.78 Hz, 1H) 10.17 (br. s., 1H) 10.70 (br. s., 1H) 11.85 (s,1H).

3-[2-[(2-Methoxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylicAcid ethyl ester dihydrochloride Formula (V),R=2-[(2-Methoxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin)-phenyl

ESI MS: m/z 596 (MH⁺);

3-[2-[((S)-2-Methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylicAcid ethyl ester dihydrochloride Formula (V),R=2-[((S)-2-Methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin)-phenyl

ESI MS: m/z 609 (MH⁺).

Example 35-(2,6-Dichloro-phenylcarbamoyl)-6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicAcid ethyl ester Formula (VII), R=4-(4-methyl-piperazin)-phenyl,Ar=2,6-dichlorophenyl, A=NH

To a solution of6,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester dihydrochloride (0.60 g, 1.20 mmol)N,N-diisopropylethylamine (0.41 ml, 2.40 mmol) in dry CH₂Cl₂ (100 mL), asolution of 1,3-dichlorophenyl isocyanate (0.14 g, 0.75 mmol) in dryCH₂Cl₂ (10 mL) was slowly added. The reaction was stirred at roomtemperature over night, then the solvent removed under reduced pressure,the residue dissolved in DCM (40 mL) and washed with water (1×20 mL).The organic phase was dried over sodium sulphate, the solvent evaporatedin vacuo, the residue suspended in ethyl ether (50 ml) and stirred for30′. The organic phase was removed under filtration yielding 0.6 g(yield 81%) of the title compound.

ESI MS: m/z 614 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ 10.74 (s, 1H), 8.30 (s, 1H), 7.84 (m, 2H),7.52 (m, 2H), 7.31 (m, 1H), 7.15 (m, 2H), 4.83 (s, 2H), 4.49 (q, 2H,J=7.0 Hz), 3.32 (m, 4H), 2.53 (s, 3H), 250 (m, 4H), 1.69 (s, 6H), 1.40(t, 3H, J=7.0 Hz).

By working in an analogous manner the following compounds were prepared:

5-(2,6-Dichloro-phenylcarbamoyl)-6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylicAcid ethyl ester Formula (VII), R=2-nitro-4-(4-methyl-piperazin)-phenyl,Ar=2,6-dichlorophenyl, A=NH

ESI MS: m/z 659(MH⁺)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (t, J=7.13 Hz, 3H), 1.82 (s, 6H),2.22 (s, 3H), 2.39-3.47 (m, 4H), 3.33-3.40 (m, 4H), 4.44 (q, J=7.13 Hz,2H), 4.69 (s, 2H), 7.21 (dd, J=8.90 and 2.56 Hz, 1H), 7.28 (t, J=7.98Hz, 1H), 7.41 (d, J=2.56 Hz, 1H), 7.48 (d, J=7.98 Hz, 2H), 7.62 (d,J=8.90 Hz, 1H), 8.24 (s, 1H), 11.62 (s, 1H).

5-(2,6-Dichloro-phenylcarbamoyl)-3-[2-[(2-methoxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylicAcid ethyl ester Formula (VII), [Formula (IV),R=2-[(2-Methoxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin)-phenyl,Ar=2,6-dichlorophenyl, A=NH

ESI MS: m/z 783(MH⁺).

5-(2,6-Dichloro-phenylcarbamoyl)-3-[2-[((S)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylicAcid ethyl ester Formula (VII),R=2-[((S)-2-Methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-4-(4-methyl-piperazin)-phenyl,Ar=2,6-dichlorophenyl, A=NH

ESI MS: m/z 797(MH⁺).

Example 45-[2-(2,6-Difluoro-phenyl)-acetyl]-6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicAcid ethyl ester Formula (VII), R=4-(4-methyl-piperazin)-phenyl,Ar=2,6-difluorophenyl, A=CH₂

To a solution of6,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester dihydrochloride (0.50 g, 1.00 mmol)N,N-diisopropylethylamine (0.68 mL, 4.00 mmol)(2,6-Difluoro-phenyl)-acetic acid (0.26 g, 1.50 mmol) in dry CH₂Cl₂ (30ml), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (0.48 g, 1.50 mmol) was added. The reaction wasstirred at room temperature over night, the solvent removed underreduced pressure, the residue dissolved in CH₂Cl₂ (40 mL) and washedwith water (1×20 mL) then with saturated sodium hydrogencarbonateaqueous solution (1×20 mL). The organic phase was dried over sodiumsulphate, the solvent evaporated in vacuo and the crude product purifiedby flash chromatography (CH₂Cl₂/MeOH 95/5) to afford 0.40 g (yield 69%)of the title compound.

ESI MS: m/z 581 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ 10.72 (s, 1H), 7.67 (s, 2H), 7.37 (m, 1H),7.15-7.05 (m, 4H), 4.98 (s, 2H), 4.48 (q, 2H, J=7.1 Hz), 3.79 (s, 2H),3.32 (m, 4H), 2.50 (m, 4H), 2.26 (s, 3H), 1.66 (s, 6H), 1.38 (t, 3H,J=7.1 Hz).

Example 56,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylicAcid (2,6-difluoro-phenyl)-amide (Comp. 3, A1-Z-B3)

To a solution of triphosgene (195 mg, 0.65 mmol, 0.56 eq) in DCM (15 mL)was added a solution of6,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester dihydrochloride (0.60 g, 1.15 mmol) in DCM (30 mL)followed by N,N-diisopropylethylamine (760 microL, 4.31 mmol, 3.75 eq).After 3 hours, a solution of 2,6-Difluoro-phenylamine (0.22, 1.72 mmol,1.5 eq) and diisopropylethylamine (300 microL, 1.72 mmol, 1.5 eq) in DCM(8 mL) was added. The reaction was stirred overnight at roomtemperature. The solution was washed with brine, the organic phase wasdried over sodium sulphate and concentrated. The residue was dissolvedin methanol (16 mL), treated with TEA (1.6 mL, 11.5 mmol, 10 eq) andstirred overnight at room temperature. After evaporation of the solvent,the solid was purified by flash chromatography (CH₂Cl₂/MeOH/NH₃95/5/01). The solid was treated with diisopropylether and filtered toafford 0.37 g of the title compound in 64% yield.

ESI MS: m/z 510 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ 12.41 (s, 1H), 10.57 (s, 1H), 8.35 (s, 1H),7.93 (m, 2H), 7.20-7.05 (m, 3H), 7.00 (m, 2H), 4.70 (s, 2H), 3.33 (m,4H), 2.46 (m, 4H), 2.24 (s, 3H), 1.68 (s, 6H).

Example 66,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylicAcid (2,6-dichloro-phenyl)-amide (Comp. 1, A1-Z-B1)

5-(2,6-Dichloro-phenylcarbamoyl)-6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester (0.6 g, 0.97 mmol) was dissolved in methanol (20 mL),treated with TEA (0.67 mL, 4.85 mmol, 5 eq) and stirred overnight atroom temperature. After evaporation of the solvent, the solid wastreated with diethyl ether and filtered to afford 0.28 g (yield 76%) ofthe title compound.

ESI MS: m/z 542 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ 12.42 (s, 1H), 10.57 (s, 1H), 8.15 (s, 1H),7.93 (m, 2H), 7.50 (m, 2H), 7.29 (m, 1H), 7.01 (m, 2H), 4.72 (s, 2H),3.35 (m, 4H), 2.52 (m, 4H), 2.32 (s, 3H), 1.68 (s, 6H).

By working in an analogous manner the following compounds were prepared:

ESI MS: N^(o) Code m/z (MH⁺) NMR data 2 A1-Z-B2 473 (400 MHz, DMSO-d₆):δ 12.39 (s, 1H), 10.58 (s, 1H), 7.89 (m, 2H), 7.31 (m, 2H), 7.28-7.22(m, 3H), 6.99 (m, 2H), 4.74 (s, 2H), 3.70 (s, 2H), 3.33 (m, 4H), 2.51(m, 4H), 2.26 (s, 3H), 1.70 (s, 6H). 4 A1-Z-B4 509 (400 MHz, DMSO-d₆): δ12.39 (s, 1H), 10.57 (s, 1H), 7.90 (m, 2H), 7.12-6.93 (m, 5H), 4.77 (s,2H), 3.78 (s, 2H), 3.29 (m, 4H), 2.44 (m, 4H), 2.22 (s, 3H), 1.68 (s,6H). 5 A1-Z-B5 509 (400 MHz, DMSO-d₆): δ 12.40 (s, 1H), 10.59 (s, 1H),7.91 (m, 2H), 7.36 (m, 1H), 7.07 (m, 2H), 6.98 (m, 2H), 4.82 (s, 2H),3.75 (s, 2H), ), 3.32 (m, 4H), 2.45 (m, 4H), 2.23 (s, 3H), 1.65 (s, 6H).6 A2-Z-B1 542 (400 MHz, DMSO-d₆): δ 12.48 (s, 1H), 10.86 (s, 1H), 8.16(s, 1H) 7.59 (s, 1H), 7.49 (m, 2H), 7.43 (m, 1H) 7.34 (m, 1H) 7.29 (m,1H), 7.15 (m, 1H), 4.74 (s, 2H), 3.23 (m, 4H), 2.51 (m, 4H), 2.24 (s,3H), 1.69 (s, 6H). 7 A3-Z-B1 536 (400 MHz, DMSO-d₆): δ 12.44 (s, 1H),10.58 (s, 1H), 8.15 (s, 1H) 7.74 (m, 1H), 7.49 (m, 3H), 7.43 (m, 2H),7.28 (m, 2H) 7.20 (m, 1H), 7.13 (m, 2H), 6.91 (m, 1H), 4.72 (s, 2H),1.67 (s, 6H). 8 A1-Z-B6 474 (400 MHz, DMSO-d₆): δ 12.40 (s, 1H), 10.56(s, 1H), 8.10 (s, 1H), 7.93 (bs, 2H), 7.54 (m, 2H), 7.24 (m, 2H), 7.00(m, 2H) 6.94 (m, 1H), 4.72 (s, 2H), 3.33 (m, 4H), 2.46 (m, 4H), 2.24 (s,3H), 1.72 (s, 6H). 9 A1-Z-B7 541 (400 MHz, DMSO-d₆): δ 12.43 (s, 1H),10.62 (s, 1H), 7.93 (bs, 2H), 7.49 (m, 2H), 7.33 (m, 1H), 7.00 (bs, 2H)4.90 (s, 2H), 4.00 (s, 2H), 3.32 (m, 4H), 2.51 (m, 4H), 2.25 (s, 3H),1.68 (s, 6H). 58 A4-Z-B1 512 (400 MHz, DMSO-d₆): δ 12.47 (s, 1H), 11.05(s, 1H), 8.19 (s, 1H), 7.98-7.60 (m, 4H), 7.49 (m, 2H), 7.29 (m, 1H),4.73 (s, 2H), 1.70 (s, 6H). 59 A2-Z-B5 509 (400 MHz, DMSO-d₆): δ 12.49(bs, 1H), 10.91 (s, 1H), 7.57 (s, 1H) 7.42 (s, 1H), 7.38 (m, 1H), 7.17(m, 1H) 7.09 (m, 2H) 4.88 (s, 2H), 3.77 (s, 2H), 3.25 (m, 4H), 2.51 (m,4H), 2.25 (s, 3H), 1.68 (s, 6H). 60 A1-Z-B56 479 (400 MHz, DMSO-d₆): δ12.40 (bs, 1H), 10.59 (s, 1H), 7.90 (m, 2H), 7.38 (m, 1H), 7.05-6.90 (m,4H), 4.76 (s, 2H), 3.92 (s, 2H), 3.07 (m, 4H), 2.50 (m, 4H), 2.30 (s,3H), 1.68 (s, 6H). 61 A5-Z-B5 469 (400 MHz, DMSO-d₆): δ 12.55 (s, 1H),11.17 (s, 1H), 8.20-8.00 (m, 4H) 7.36 (s, 1H), 7.07 (m, 2H), 4.88 (s,2H), 3.90 (s, 3H), 3.75 (s, 2H), 1.67 (s, 6H). 104 A47-Z-B5 429 (400MHz, DMSO-d₆): δ 12.89 (s, 1H), 10.46 (s, 1H), 7.86 (m, 1H) 7.57 (s,1H), 7.34 (m, 3H), 7.07 (m, 2H), 4.89 (s, 2H), 3.75 (s, 2H), 1.67 (s,6H). 106 A4-Z-B5 479 ¹H NMR (400 MHz, DMSO-d₆): δ 12.48 (s, 1H), 11.08(s, 1H), 7.85-7.60 (m, 4H), 7.36 (m, 1H), 7.08 (m, 2H), 4.84 (s, 2H),3.74 (s, 2H), 1.67 (s, 6H). 185 A89-Z-B1 502 (400 MHz, DMSO-d₆) δ ppm1.68 (s, 6H) 3.90 (s, 3H) 4.74 (s, 2H) 7.28 (dd, J = 8.41, 7.80 Hz, 1H)7.47-7.51 (m, 2H) 7.68 (t, J = 7.56 Hz, 1H) 8.07-8.20 (m, 1H) 8.29 (d, J= 7.80 Hz, 1H) 8.60-8.63 (m, 1H) 11.19 (br. s., 1H) 12.53 (br. s., 1H)186 A90-Z-B1 502 (40 MHz, DMSO-d₆) δ ppm 1.69 (s, 6H) 3.90 (s, 3H) 4.74(br. s., 2H) 7.29 (dd, J = 8.41, 7.80 Hz, 1H) 7.50 (d, J = 8.05 Hz, 2H)7.99-8.27 (m, 5H) 11.13 (s, 1H) 12.54 (br. s., 1H) 236 A17-Z-B6 376 (400MHz, DMSO-d₆): δ 12.49 (bs, 1H), 10.90 (s, 1H), 8.11 (s, 1H), 8.03 (m,2H), 7.61 (m, 1H), 7.55 (m, 2H), 7.52 (m, 2H), 7.24 (m, 2H), 6.94 (m,1H), 4.75 (m, 2H), 1.73 (s, 6H). 237 A17-Z-B2 375 (400 MHz, DMSO-d₆): δ12.48 (bs, 1H), 10.02 (s, 1H), 7.99 (m, 2H), 7.60 (m, 1H), 7.51 (m, 2H),7.31 (m, 2H), 7.26 (m, 3H), 4.76 (s, 2H), 3.71 (s, 2H), 1.71 (s, 6H).239 A73-Z-B1 480 (400 MHz, DMSO-d₆): δ 12.54 (s, 1H), 11.28 (s, 1H),8.20 (s, 1H), 7.57 (m, 1H), 7.49 (m, 2H), 7.29 (m, 1H), 7.22 (m, 2H),4.75 (m, 2H), 1.70 (s, 6H). 241 A75-Z-B1 487 (400 MHz, DMSO-d₆) δ ppm1.68 (s, 6H) 4.74 (br. s., 2H) 7.28 (dd, J = 8.35, 7.87 Hz, 1H)7.46-7.52 (m, 3H) 7.92-8.19 (m, 6H) 11.02 (br. s., 1H) 12.51 (br. s.,1H) 244 A78-Z-B1 522 (400 MHz, DMSO-d₆): δ 12.53 (s, 1H), 11.22 (s, 1H),8.23 (m, 2H) 8.16 (s, 1H), 8.05 (m, 2H), 7.49 (m, 2H) 7.28 (m, 1H), 4.75(s, 2H), 3.30 (s, 3H), 1.69 (s, 6H). 249 A83-Z-B1 584 (400 MHz,DMSO-d₆): δ 12.50 (s, 1H), 10.87 (s, 1H), 10.16 (s, 1H), 8.31 (m, 1H),8.15 (bs. s., 1H), 7-66-7-77 (m, 2H), 7.51 (m, 2H), 7.39-7.47 (m, 1H)7.26-7.34 (m, 1H), 4.74 (s, 2H), 3.25-3.43 (m, 2H), 3.18 (m, 1H),2.42-2.62 (m, 2H), 2.52 (s, 3H), 1.88-1.98 (m, 2H), 1.75-1.97 (m, 2H),1.69 (s, 6H). 250 A84-Z-B1 459 (400 MHz, DMSO-d₆) δ ppm 1.66 (s, 6H)4.68 (s, 2H) 5.26 (br. s., 2H) 6.69-6.77 (m, 1H) 7.07-7.15 (m, 3H)7.22-7.30 (m, 1H) 7.44-7.51 (m, 2H) 8.10 (br. s., 1H) 10.59 (br. s., 1H)12.41 (br. s., 1H) 251 A85-Z-B1 459 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.66(br. s., 6H) 4.68 (br. s., 2H) 5.72 (bs. s., 2H), 6.51-6.64 (m, 2H),7.27 (t, J = 8.05 Hz, 1H) 7.48 (d, J = 7.80 Hz, 2H), 7.65-7.81 (m, 2H),8.12 (s, 1H), 10.32 (s, 1H), 12.33 (s, 1H), 253 A87-Z-B1 507 (400 MHz,DMSO-d₆) δ ppm 1.68 (s, 6H) 4.74 (s, 2H) 7.24-7.31 (m, 1H) 7.46-7.52 (m,2H) 7.71-7.79 (m, 1H) 8.15 (br. s., 1H) 8.44 (d, J = 7.19 Hz, 1H) 8.82(d, J = 7.56 Hz, 1H) 11.34 (s, 1H) 12.58 (s, 1H) 255 A91-Z-B1 580 — 259A1-Z- 546 (400 MHz, DMSO-d6): δ 1.68 (s, 6H) 2.30 (s, 3H) 2.87 (s, 3H)B113 3.00-3.22 (m, 4H) 3.53 (d, J = 9.02 Hz, 2H) 4.06 (d, J = 10.24 Hz,2H) 4.65 (s, 2H) 6.51 (s, 1H) 7.09 (d, J = 8.90 Hz, 2H) 7.89 (s, 1H)7.97 (d, J = 8.90 Hz, 2H) 9.70 (br. s., 1H) 10.67 (s, 1H) 12.43 (br. s.,1H) 260 A1-Z- 480 (400 MHz, DMSO-d6): δ 1.70 (s, 6H) 2.87 (s, 3H) B1143.01-3.20 (m, 4H) 3.53 (d, J = 9.15 Hz, 2H) 4.06 (d, J = 12.56 Hz, 2H)4.65 (s, 2H) 7.06-7.11 (m, 2H) 7.21-7.24 (m, 1H) 7.31-7.36 (m, 2H) 7.97(d, J = 9.02 Hz, 2H) 8.53 (s, 1H) 9.69 (br. s., 1H) 10.64 (s, 1H) 261A1-Z- 493 (400 MHz, DMSO-d6): δ 1.67 (s, 6H) 2.09 (s, 3H) 2.26 (s, 3H)B115 2.88 (s, 3H) 3.01-3.22 (m, 4H) 3.54 (d, J = 11.10 Hz, 2H) 4.06 (d,J = 11.95 Hz, 2H) 4.65 (s, 2H) 7.09 (d, J = 9.02 Hz, 2H) 7.59 (s, 1H)7.97 (d, J = 8.90 Hz, 2H) 9.69 (br. s., 1H) 10.65 (s, 1H) 262 A1-Z- 499(400 MHz, DMSO-d6): δ 1.70 (s, 6H) 2.87 (s, 3H) B116 3.01-3.21 (m, 4H)3.49-3.56 (m, 2H) 4.06 (d, J = 11.95 Hz, 2H) 4.75 (s, 2H) 7.08 (d, J =9.02 Hz, 2H) 7.22-7.27 (m, 1H) 7.52 (d, J = 7.56 Hz, 1H) 7.59-7.65 (m,1H) 7.73 (dd, J = 7.80, 1.34 Hz, 1H) 7.97 (d, J = 9.02 Hz, 2H) 8.51 (s,1H) 9.68 (br. s., 1H) 10.68 (s, 1H) 263 A1-Z- 480 (400 MHz, DMSO-d6): δ1.70 (s, 6H) 2.87 (s, 3H) B117 3.00-3.22 (m, 4H) 3.53 (d, J = 10.61 Hz,2H) 4.06 (d, J = 13.17 Hz, 2H) 4.66 (s, 2H) 6.71 (dd, J = 3.05, 2.07 Hz,1H) 6.75-6.79 (m, 2H) 7.05-7.12 (m, 2H) 7.98 (d, J = 9.02 Hz, 2H) 9.37(s, 1H) 9.69 (br. s., 1H) 10.66 (s, 1H). 264 A1-Z- 543 (400 MHz,DMSO-d6): δ 1.71 (s, 6H), 2.87 (s, 3H) B118 2.99-3.27 (m, 4H) 3.50-3.55(m, 2H) 4.06 (d, J = 13.17 Hz, 2H) 4.75 (s, 2H) 7.05-7.10 (m, 2H) 7.77(s, 2H) 7.97 (d, J = 9.02 Hz, 2H) 9.03 (s, 1H) 9.69 (br. s., 1H) 10.69(s, 1H). 265 A1-Z- 568 (400 MHz, DMSO-d6): δ 1.69 (s, 6H), 2.26 (s, 3H),2.88 (b.s., B119 3H), 3.00-3.25 (m, 4H), 3.48-3.59 (m, 2H), 4.06 (d, J =13.29 Hz, 2H), 4.71 (s, 2H), 7.05-7.13 (m, 3H), 7.25 (d, J = 6.83 Hz,1H), 7.48 (d, J = 7.93 Hz, 1H), 7.80 (s, 1H), 7.98 (d, J = 9.02 Hz, 2H),9.70 (b.s., 1H), 10.65 (s, 1H). 266 A1-Z- 509 (400 MHz, DMSO-d6): δ 1.72(s, 6H), 2.88 (b.s., 3H), B120 3.04-3.21 (m, 4H), 3.49-3.60 (m, 2H),4.07 (d, J = 7.32 Hz, 2H), 4.77 (s, 2H), 7.05-7.13 (m, 2H), 7.41 (dd, J= 7.99 and 4.69 Hz, 1H), 7.78 (s, 1H), 7.98 (d, J = 9.02 Hz, 2H), 8.13(dd, J = 4.69 and 1.83 Hz, 1H), 8.18 (dd, J = 7.99 and 1.83 Hz, 1H),9.68 (b.s., 1H), 10.71 (s, 1H). 267 A1-Z- 526 (400 MHz, DMSO-d6): δ 1.68(s, 6H), 2.88 (b.s., 3H), B121 2.97-3.21 (m, 4H), 3.48-3.68 (m, 2H),3.99-4.16 (m, 2H), 4.71 (s, 2H), 7.09 (d, J = 9.02 Hz, 2H), 7.20-7.41(m, 3H), 7.97 (d, J = 8.01 Hz, 2H), 9.72 (b.s., 1H), 10.66 (s, 1H). 268A1-Z- 571 (400 MHz, DMSO-d6): δ 1.68 (s, 6H), 2.88 (b.s., 3H), B1222.98-3.24 (m, 4H), 3.47-3.61 (m, 2H), 3.99-4.13 (m, 2H), 4.71 (s, 2H),7.05-7.14 (m, 2H), 7.20-7.32 (m, 2H), 7.48-7.53 (m, 1H), 7.93-8.03 (m,3H), 9.70 (b.s., 1H), 10.66 (s, 1H). 275 A94-Z-B1 587 (400 MHz, DMSO-d6)δ ppm 1.67 (s, 6H) 2.23 (s, 3H) 2.41-2.46 (m, 4H) 3.30-3.38 (m, 4H) 4.65(br. s., 2H) 7.21 (d, J = 7.93 Hz, 1H) 7.24-7.30 (m, 1H) 7.39 (br. s.,1H) 7.44-7.51 (m, 2H) 7.60 (d, J = 8.41 Hz, 1H) 8.15 (br. s., 1H) 11.01(br. s., 1H) 12.44 (s, 1H) 240 A95-Z-B1 615 (400 MHz, DMSO-d6) δ ppm1.68 (br. s., 6H) 2.22 (s, 3H) 2.40-2.45 (m, 4H) 3.25-3.28 (m, 4H) 3.29(s, 3H) 3.32 (br. s., 6H) 3.53 (t, J = 5.30 Hz, 2H) 4.63 (br. s., 2H)6.08 (s, 1H) 6.20 (br. s., 1H) 7.25-7.32 (m, 1H) 7.48-7.52 (m, 2H) 10.20(br. s., 1H)

Example 73-Amino-5-(2,6-dichloro-phenylcarbamoyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicAcid ethyl ester Formula (XI), Ar=2,6-dichlorophenyl, A=NH

To a solution of3-amino-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester dihydrochloride (4.0 g, 15.30 mmol)N,N-diisopropylethylamine (10.6 ml, 61.00 mmol) in dry THF (50 mL)cooled at 0° C., a solution of 1,3-dichlorophenyl isocyanate (3.16 g,16.80 mmol) in dry THF (10 mL) was slowly added. The reaction wasstirred at room temperature for 4 h, then the solvent removed underreduced pressure, the residue dissolved in DCM (100 mL) and washed with0.1N hydrochloric acid solution water (1×20 mL) and with brine (1×20mL). The organic phase was dried over sodium sulphate, the solventevaporated in vacuo, the residue suspended in ethyl ether (50 mL) andstirred for 30′. The organic phase was removed under filtration yielding4.5 g (yield 71%) of the title compound as white solid.

ESI MS: m/z 412 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ 7.99 (s, 1H), 7.52 (m, 2H), 7.31 (m, 1H),6.61 (bs, 2H), 4.39 (s, 2H), 4.37 (q, 2H, J=7.0 Hz), 1.62 (s, 6H), 1.35(t, 3H, J=7.0 Hz).

Example 83-Amino-5-[2-(2,6-difluoro-phenyl)-acetyl]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicAcid ethyl ester Formula (XI), Ar=2,6-difluorophenyl, A=CH₂

To a solution of3-amino-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester dihydrochloride (4.5 g, 17.20 mmol)N,N-diisopropylethylamine (12.00 mL, 68.80 mmol)(2,6-Difluoro-phenyl)-acetic acid (4.45 g, 28.50 mmol) in dry CH₂Cl₂ (30ml) cooled in an ice bath,O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(9.15 g, 28.50 mmol) was added. At the end of the addition the reactionwas allowed to reach room temperature and stirred over night. Thesolvent was removed under reduced pressure, the residue dissolved inCH₂Cl₂ (40 mL) and washed with water (1×50 mL), 0.1N hydrochloric acidsolution water (1×50 mL), sodium hydrogencarbonate aqueous solution(1×50 mL) and finally with brine (1×50 mL). The organic phase was driedover sodium sulphate, the solvent evaporated in vacuo and the residuesuspended in ethyl ether (50 mL) and stirred for 30′. The organic phasewas removed under filtration yielding 4.5 g (yield 69%) of the titlecompound as white solid.

ESI MS: m/z 379 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ 7.36 (m, 1H), 7.07 (m, 2H), 6.63 (s, 2H),4.53 (s, 2H), 4.36 (q, 2H, J=7.2 Hz), 3.72 (s, 2H), 1.59 (s, 6H), 1.33(t, 3H, J=7.2 Hz).

Example 95-(2,6-Dichloro-phenylcarbamoyl)-6,6-dimethyl-3-(2-trifluoromethyl-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicAcid ethyl ester Formula (VII), R=2-trifluorophenyl,Ar=2,6-dichlorophenyl, A=NH

To a solution of3-Amino-5-(2,6-dichloro-phenylcarbamoyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester (0.20 g, 0.53 mmol), N,N-diisopropylethylamine (0.40mL, 2.30 mmol) in anhydrous THF (20 mL), 2-trifluoromethyl-benzoylchloride (0.88 mL, 0.60 mmol) was added. The reaction was heated toreflux and stirred for 6 h. The solvent was removed under vacuum and thecrude residue purified by flash chromatography affording 0.22 g (yield71%) of the title compound.

ESI MS: m/z 584 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ 11.03 (s, 1H), 8.20 (s, 1H), 7.95-7.60 (m,4H), 7.47 (m, 2H), 7.31 (m, 1H), 4.73 (s, 2H), 4.47 (q, 2H, J=7.1 Hz),1.70 (s, 6H), 1.35 (t, 3H, J=7.1 Hz).

By working in an analogous manner the following compounds were prepared:

5-[2-(2,6-Difluoro-phenyl)-acetyl]-6,6-dimethyl-3-(2-trifluoromethyl-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicAcid ethyl ester Formula (VII), R=2-trifluorophenyl,Ar=2,6-difluorophenyl, A=CH₂

ESI MS: m/z 551 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ 11.05 (s, 1H), 7.80-7.60 (m, 4H), 7.36 (m,1H), 7.10 (m, 2H), 4.46 (q, 2H, J=7.1 Hz), 4.84 (s, 2H), 3.74 (s, 2H),1.65 (s, 6H), 1.36 (t, 3H, J=7.1 Hz).

5-(2,6-Dichloro-phenylcarbamoyl)-3-(4-methoxycarbonyl-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicAcid ethyl ester Formula (VII), R=4-methoxycarbonylphenyl,Ar=2,6-dichlorophenyl, A=NH

ESI MS: m/z 574 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ 10.97 (s, 1H), 8.29 (s, 1H), 8.18 (m, 2H),8.06 (m, 2H), 7.50 (m, 2H), 7.30 (m, 1H), 4.81 (s, 2H), 4.48 (q, 2H,J=7.1 Hz), 3.91 (s, 3H), 1.69 (s, 6H), 1.38 (t, 3H, J=7.1 Hz).

3-(4-Nitro-benzoylamino)-5-(2,6-dichloro-phenylcarbamoyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicAcid ethyl ester Formula (VII), R=4-nitrophenyl, Ar=2,6-dichlorophenyl,A=NH

ESI MS: m/z 561 (MH⁺)731

3-(3-Nitro-4-fluoro-benzoylamino)-5-(2,6-dichloro-phenylcarbamoyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicAcid ethyl ester Formula (VII), R=3-nitro,4-fluorophenyl,Ar=2,6-dichlorophenyl, A=NH

ESI MS: m/z 579(MH⁺)

Example 10N-[5-(2,6-Dichloro-phenylcarbamoyl)-6,6-dimethyl-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-terephthalamicAcid (Comp. 127, A6-Z-B1)

To a solution of5-(2,6-Dichloro-phenylcarbamoyl)-3-(4-methoxycarbonyl-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester (0.4 g, 0.74 mmol) in methanol (5 mL), 2N NaOH aqueoussolution (1.00 mL, 2.00 mmol) was added and warmed to 70° C. After 4hours stirring, water was added (20 mL) and the aqueous solutionextracted with ethyl acetate (1×20 mL). The aqueous phase was acidifiedwith 1N HCl solution and extracted with ethyl acetate (2×20 mL). Thecombined organic phases were dried over sodium sulphate, the solventevaporated in vacuo yielding 0.33 g (yield 91%) of the title compound aswhite solid.

ESI MS: m/z 488 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ 13.4-12.4 (bs, 2H), 11.09 (s, 1H), 8.13(bs, 1H), 8.11-8.03 (m, 4H), 7.49 (m, 2H), 7.28 (m, 1H), 4.73 (s, 2H),1.68 (s, 6H).

By working in an analogous manner the following compounds were prepared:

ESI MS: m/z N^(o) Code (MH⁺) NMR data 62 A6-Z-B5 455 (400 MHz, DMSO-d₆):δ 13.50-12.00 (bs, 1H), 11.14 (s, 1H), 8.11 (m, 2H), 8.03 (m, 2H), 7.35(m, 1H), 7.07 (m, 2H), 4.88 (s, 2H), 3.76 (s, 2H), 1.67 (s, 6H). 245A79-Z-B1 488 (400 MHz, DMSO-d₆) δ ppm 1.70 (s, 6H) 4.74 (s, 2H)7.26-7.33 (m, 1H) 7.48-7.53 (m, 2H) 7.67 (t, J = 7.80 Hz, 1H) 8.12-8.17(m, 2H) 8.26 (d, J = 7.80 Hz, 1H) 8.60 (t, J = 1.52 Hz, 1H) 11.14 (s,1H) 12.66 (br. s., 1H) 256 A74-Z-B1 524

Example 11N-[5-(2,6-Dichloro-phenylcarbamoyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-N′-(1-methyl-piperidin-4-yl)-terephthalamide(Comp. 238, A72-Z-B1)

To a solution ofN-[5-(2,6-Dichloro-phenylcarbamoyl)-6,6-dimethyl-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-terephthalamicacid (0.1 g, 0.22 mmol) N,N-diisopropylethylamine (0.12 mL, 0.66 mmol)1-Methyl-piperidin-4-ylamine (0.04 g, 0.34 mmol) in dry CH₂Cl₂ (20 mL),O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.11 g, 0.34 mmol) was added. The reaction was stirred at roomtemperature over night, the solvent removed under reduced pressure, theresidue dissolved in CH₂Cl₂ (40 mL) and washed with water (1×20 mL) thenwith saturated sodium hydrogencarbonate aqueous solution (1×20 mL). Theorganic phase was dried over sodium sulphate, the solvent evaporated invacuo and the crude product purified by flash chromatography(CH₂Cl₂/MeOH/NH₃ 90/10/1) to afford 0.07 g (yield 55%) of the titlecompound.

ESI MS: m/z 584 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ 12.53 (s, 1H), 11.04 (s, 1H), 8.38 (d, 1H,J=7.6 Hz), 8.14 (s, 1H), 8.10-7.90 (m, 4H), 7.49 (m, 2H), 7.28 (m, 1H),4.73 (s, 2H), 3.75 (m, 1H), 3.78 (m, 2H), 2.17 (s, 3H), 1.97 (m, 2H),1.77 (m, 2H), 1.68 (s, 6H), 1.58 (m, 2H).

By working in an analogous manner the following compounds were prepared:

ESI MS: N^(o) Code m/z (MH⁺) NMR data 128 A69-Z-B5 525 (400 MHz,DMSO-d6): δ 12.53 (s, 1H), 11.07 (s, 1H), 8.54 (m, 1H), 8.08 (m, 2H),7.93 (m, 2H), 7.34 (m, 1H), 7.07 (m, 2H), 4.89 (s, 2H), 3.76 (s, 2H),3.39 (m, 2H), 2.50 (m, 2H), 2.33 (s, 6H), 1.67 (s, 6H). 233 A71-Z-B5 539(400 MHz, DMSO-d₆): δ 12.55 (s, 1H), 11.08 (s, 1H), 8.65 (m, 1H), 8.09(m, 2H), 7.95 (m, 2H), 7.38 (m, 1H), 7.09 (m, 2H), 4.91 (s, 2H), 3.77(s, 2H), 3.33 (m, 2H), 2.28 (t, J = 6.7 Hz, 2H), 2.16 (s, 6H), 1.68 (m,8H). 234 A72-Z-B5 551 (400 MHz, DMSO-d₆): δ 12.54 (s, 1H), 11.07 (s,1H), 8.39 (d, J = 7.5 Hz, 1H), 8.09 (m, 2H), 7.94 (m, 2H), 7.36 (m, 1H),7.07 (m, 2H), 4.89 (s, 2H), 3.77 (m, 1H), 3.76 (s, 2H), 2.81 (m, 2H),2.20 (s, 3H), 2.01 (m, 2H), 1.80 (m, 2H), 1.67 (s, 6H), 1.61 (m, 2H).235 A71-Z-B1 572 (400 MHz, DMSO-d₆): δ 12.52 (bs, 1H), 11.04 (s, 1H),8.66 (t, J = 6.0 Hz, 1H), 8.13 (s, 1H), 8.08 (m, 2H), 7.94 (m, 2H), 7.50(m, 2H), 7.28 (m, 1H), 4.73 (s, 2H), 3.32 (m, 2H), 2.50 (m, 2H), 2.32(s, 6H), 1.73 (m, 2H), 1.68 (m, 6H). 243 A77-Z-B1 584 (400 MHz, DMSO-d₆)δ ppm 1.68 (s, 6H) 1.79-1.94 (m, 2H) 1.99-2.10 (m, 2H) 2.58-2.67 (m, 1H)2.79 (s, 3H) 2.89-3.01 (m, 2H) 3.44-3.54 (m, 2H) 4.72 (br. s., 2H)7.23-7.33 (m, 1H) 7.45-7.52 (m, 2H) 7.72 (d, J = 8.54 Hz, 2H) 8.00 (d, J= 8.05 Hz, 2H) 8.14 (br. s., 1H) 9.40 (br. s., 1H) 10.34 (br. s., 1H)10.78 (br. s., 1H) 12.47 (br. s., 1H) 246 A80-Z-B1 487 (400 MHz,DMSO-d₆) δ ppm 12.51 (br. s., 1H), 10.93 (br. s., 1H), 8.51 (s, 1H),7.93-8.21 (m, 3H), 7.59 (m, 1H), 7.49 (m, 2H), 7.28 (m, 1H), 4.74 (br.s., 2H), 1.68 (s, 6H). 247 A81-Z-B1 584 (400 MHz, DMSO-d₆) δ ppm 12.52(br. s., 1H), 10.94 (br. s., 1H), 8.44 (br. s., 1H), 8.36 (br. s., 1H),8.10-8.18 (m, 2H), 7.62 (m, 1H), 7.49 (m, 2H), 7.26-7.30 (m, 1H), 4.75(br. s., 2H), 3.74-3.85 (br. s. 1H), 2.81-2.94 (br. s. 2H), 2.25 (s,3H), 2.06-2.14 (br. s., 2H), 1.77-1.86 (m, 2H), 1.68 (s, 6H), 1.58-1.65(m, 2H).

Example 123-[3-Amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-6,6-dimethyl-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylicAcid (2,6-dichloro-phenyl)-amide (Comp. 252, A86-Z-B1)

To a solution of3-(3-Nitro-4-fluoro-benzoylamino)-5-(2,6-dichloro-phenylcarbamoyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester (0.28 g, 0.48 mmol) in dry THF (10 mL),N-methylpiperazine (0.16 L, 1.40 mmol) was added. The reaction wasstirred at room temperature for four hours, the solvent removed underreduced pressure and the crude product purified by flash chromatography(CH₂Cl₂/MeOH 90/10) to afford 0.20 g (yield 70%) of the title compound.

ESI MS: m/z 587 (MH⁺);

¹H NMR (401 MHz, DMSO-d₆) δ ppm 1.69 (s, 6H) 2.21-2.24 (m, 3H) 2.42-2.46(m, 4H) 3.10-3.17 (m, 4H) 4.73 (s, 2H) 7.25-7.32 (m, 1H) 7.35 (d, J=8.66Hz, 1H) 7.46-7.52 (m, 2H) 8.15 (s, 1H) 8.20 (d, J=8.66 Hz, 1H) 8.52 (d,J=1.71 Hz, 1H) 11.02 (s, 1H) 12.51 (s, 1H)

Example 133-(4-Amino-benzoylamino)-5-(2,6-dichloro-phenylcarbamoyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicAcid ethyl ester Formula (VII), R=4-aminophenyl, Ar=2,6-dichlorophenyl,A=NH

To a solution of3-(4-Nitro-benzoylamino)-5-(2,6-dichloro-phenylcarbamoyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester (0.30 g, 0.53 mmol) and 10% Pd/C in EtOH (10 mL) keptto reflux, cicloexene (1 mL) was added. The reaction was refluxed fortwo hours, the catalyst removed by filtration through a pad of celite,the solvent concentrated under reduced pressure and the crude productpurified by flash chromatography (eluant: CH₂Cl₂/Acetone 90/10) toafford 0.16 g (yield 56%) of the title compound as a yellow solid

ESI MS: m/z 531 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.41 (m, 3H) 1.66 (s, 6H) 4.47 (q,J=7.07 Hz, 2H) 4.80 (s, 2H) 6.03 (s, 2H) 6.63-6.67 (m, 2H) 7.28 (dd,J=8.35, 7.87 Hz, 1H) 7.47-7.51 (m, 2H) 7.61 (d, J=8.78 Hz, 2H) 8.27 (s,1H) 10.60 (s, 1H)

By working in an analogous manner the following compound was prepared:

ESI MS: N^(o) Code m/z (MH⁺) NMR data 254 A88-Z-B1 557 (400 MHz,DMSO-d₆) δ ppm 1.66 (s, 6H), 2.26 (s, 3H), 2.49-2.53 (m, 4H), 2.87 (m,4H), 4.69 (s, 1H) 4.84 (br. s., 1H) 6.92-6.97 (m, 1H) 7.23-7.31 (m, 3H)7.46-7.50 (m, 2H) 8.11 (br. s., 1H) 8.15 (s, 1H) 10.53 (br. s., 1H)12.34 (br. s., 1H)

Example 14N-[5-(2,6-Dichloro-phenylcarbamoyl)-6,6-dimethyl-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-N′-hydroxy-terephthalamide(Comp. 242, A76-Z-B1)

To a solution ofN-[5-(2,6-Dichloro-phenylcarbamoyl)-6,6-dimethyl-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-terephthalamicacid (0.60 g, 1.22 mmol) O-(Tetrahydro-pyran-4-yl)-hydroxylamine (0.30g, 2.56 mmol) in dry CH₂Cl₂ (20 mL),O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.60 g, 1.84 mmol) was added. The reaction was stirred four hour atroom temperature, diluted with DCM (30 mL) and washed with 05N HCl (1×20mL), then with saturated sodium hydrogencarbonate aqueous solution (1×20mL) and finally with brine (1×20 mL). The organic phase was dried oversodium sulphate, the solvent evaporated in vacuo and the crude productpurified by flash chromatography (CH₂Cl₂/MeOH₃ 90/10) to afford thetetrahydropyranyl intermediate which was dissolved in MeOH (10 ml) andadded of 2N HCl (1 mL). The reaction was stirred at room temperatureover night, the solvent removed under reduced pressure and the residuesuspended in DCM (20 mL). The suspension was stirred for 30′, the solvedallowed by filtration to yield 32 mg of the title compound as a paleyellow solid (yield 49%).

ESI MS: m/z 503 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.69 (s, 6H) 4.75 (br. s., 2H) 7.29(dd, J=8.41, 7.80 Hz, 1H) 7.50 (d, J=8.05 Hz, 2H) 7.87 (d, J=8.05 Hz,2H) 8.08 (d, J=8.29 Hz, 2H) 8.16 (br. s., 1H) 9.22 (s, 1H) 11.03 (br.s., 1H) 11.40 (br. s., 1H) 12.53 (br. s., 1H)

By working in an analogous manner the following compound was prepared:

ESI MS: N^(o) Code m/z (MH⁺) NMR data 248 A82-Z-B1 503 (400 MHz,DMSO-d₆) δ ppm 11.27 (br. s., 1H), 10.99 (s, 1H), 8.39 (t, J = 1.46 Hz,1H), 8.09-8.15 (m, 2H), 7.88-7.95 (m, 1H), 7.60 (t, J = 7.80 Hz, 1H),7.46-7.51 (m, 2H), 7.25-7.31 (m, 1H), 4.73 (s, 2H), 1.68 (s, 6H).

Example 156,6-Dimethyl-3-[4-(4-methyl-4-oxy-piperazin-1-yl)-benzoylamino]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carboxylicAcid (2,6-dichloro-phenyl)-amide (Comp. 257, A92-Z-B1)

To a solution of6,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylicacid (2,6-dichloro-phenyl)-amide (0.30 g, 0.54 mmol) in a 1:1DCM/acetone mixture (20 mL), 0.1 M solution of dimethyldioxirane (10 mL)(prepared as described in J. Org. Chem 1987, 52, 1800) was added. Thereaction was stirred at room temperature for 1 h, the solvent evaporatedin vacuo and the crude product purified by flash chromatography(CH₂Cl₂/MeOH₃/NH₃ 85/15/0.2) yielding 0.23 g of the title compound as awhite solid (yield=73%).

ESI MS: m/z 558 (MH⁺);

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.67 (s, 6H) 3.03 (d, J=9.88 Hz, 2H)3.13 (s, 3H) 3.42-3.58 (m, 4H) 3.72 (d, J=12.19 Hz, 2H) 4.70 (br. s.,2H) 7.06 (br. s., 2H) 7.28 (dd, J=8.41, 7.80 Hz, 1H) 7.46-7.51 (m, 2H)7.93 (br. s., 2H) 8.12 (br. s., 1H) 10.62 (s, 1H) 12.42 (br. s., 1H)

By working in an analogous manner with a 5 fold excess ofdimethyldioxirare and increasing the reaction time to 12 hours, thefollowing compound was prepared:

ESI MS: N^(o) Code m/z (MH⁺) NMR data 258 A93-Z-B1 574 (400 MHz,DMSO-d₆) δ ppm 1.68 (s, 6H) 3.24 (s, 3H) 4.74 (s, 2H) 7.28 (dd, J =8.41, 7.80 Hz, 1H) 7.42-7.53 (m, 2H) 8.15 (d, J = 8.66 Hz, 3H) 8.27 (d,J = 10.24 Hz, 2H) 11.11 (br. s., 1H) 12.54 (br. s., 1H)

Purification

Several compounds of the invention of formula (I), being prepared asformerly reported, were purified by preparative HPLC.

The operative conditions are reported below:

Example 166,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-2,6-dihydro-4Hpyrrolo[3,4-c]pyrazole-5-carboxylicAcid (2-chloro-6-fluoro-phenyl)-amide (Comp 267, A1-Z-B121)

To a solution of di-tert-butyl dicarbonate (101 mg, 0.46 mmol, 1.1 eq)in DCM (2 mL) was added 2-chloro-6-fluoroaniline (61 mg, 0.42 mmol, 1eq) and N,N-dimethylpyridin-4-amine (51 mg, 0.42 mmol, 1 eq). After 1hour of agitation at room temperature,6,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4Hpyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester dihydrochloride (189 mg, 0.38 mmol, 0.9 eq),triethylamine (0.23 mL, 1.68 mmol, 4 eq) and an additional 2 mL of DCM(4 mL total). The cocktail was placed in a Personal Chemistry, SmithCreator microwave reaction station and the vial contents were irradiatedat 125° C. for 10 minutes with application of continuous, simultaneouscooling. After the 10 minutes of heating time had elapsed, the solutionwas washed twice with water. The organic phase was collected and thesolvent was removed in vacuo. The residue was dissolved in methanol (3mL), treated with triethylamine (0.3 mL, 2.2 mmol, 5 eq) and agitatedfor 6 hours at 50° C. After evaporation of the solvent, the solid waspurified by preparative HPLC to afford 0.012 g of the title compound in5% overall yield.

ESI MS: m/z 526(MH⁺)

¹H NMR (400 MHz, DMSO-d₆): δ 1.68 (s, 6H), 2.88 (b.s., 3H), 2.97-3.21(m, 4H), 3.48-3.68 (m, 2H), 3.99-4.16 (m, 2H), 4.71 (s, 2H), 7.09 (d,J=9.02 Hz, 2H), 7.20-7.41 (m, 3H), 7.97 (d, J=8.01 Hz, 2H), 9.72 (b.s.,1H), 10.66 (s, 1H).

By working in an analogous manner the following compounds were prepared:

ESI MS: N^(o) Code m/z (MH⁺) NMR data 265 A1-Z-B119 568 (400 MHz,DMSO-d₆): δ 1.69 (s, 6H), 2.26 (s, 3H), 2.88 (b.s., 3H), 3.00-3.25 (m,4H), 3.48-3.59 (m, 2H), 4.06 (d, J = 13.29 Hz, 2H), 4.71 (s, 2H),7.05-7.13 (m, 3H), 7.25 (d, J = 6.83 Hz, 1H), 7.48 (d, J = 7.93 Hz, 1H),7.80 (s, 1H), 7.98 (d, J = 9.02 Hz, 2H), 9.70 (b.s., 1H), 10.65 (s, 1H).266 A1-Z-B120 509 (400 MHz, DMSO-d₆): δ 1.72 (s, 6H), 2.88 (b.s., 3H),3.04-3.21 (m, 4H), 3.49-3.60 (m, 2H), 4.07 (d, J = 7.32 Hz, 2H), 4.77(s, 2H), 7.05-7.13 (m, 2H), 7.41 (dd, J = 7.99 and 4.69 Hz, 1H), 7.78(s, 1H), 7.98 (d, J = 9.02 Hz, 2H), 8.13 (dd, J = 4.69 and 1.83 Hz, 1H),8.18 (dd, J = 7.99 and 1.83 Hz, 1H), 9.68 (b.s., 1H), 10.71 (s, 1H). 268A1-Z-B122 571 (400 MHz, DMSO-d₆): δ 1.68 (s, 6H), 2.88 (b.s., 3H),2.98-3.24 (m, 4H), 3.47-3.61 (m, 2H), 3.99-4.13 (m, 2H), 4.71 (s, 2H),7.05-7.14 (m, 2H), 7.20-7.32 (m, 2H), 7.48-7.53 (m, 1H), 7.93-8.03 (m,3H), 9.70 (b.s., 1H), 10.66 (s, 1H).

HPLC N^(o) Code r.t. (min) [M + H]⁺ Method 269 A1-Z-B123 3.8 578 2 270A1-Z-B124 3.5 587 2 271 A1-Z-B125 3.6 577 2 272 A1-Z-B126 3.0 621 2 273A1-Z-B127 3.8 579 2 274 A1-Z-B128 4.2 626 2

Example 17

Semi-preparative HPLC purification was performed on the Biotage ParallexFlex 4-channel parallel purification system equipped with four RP₁₈X-Terra Waters columns (19×100 mm, 55 μm). Data for each purificationcycle was monitored by two wavelengths (λ=220 nm and 254 nm) wherefraction collection was triggered by UV absorbance at 254 nm.

HPLC was carried out at 25° C. at a flow rate of 20 ml/min using asmobile phase A water containing 0.1% formic acid and 2% acetonitrile andas mobile phase B acetonitrile.

Two solvents gradients (a) or (b) where used:

a) 0% B for 1 minute, then to 30% B over 6 min and finally to 100% Bover 2 minutes

b) 0% B for 1 minute, then to 40% B over 6 min and finally to 100% Bover 2 minutes.

The injection volume was 1.5 mL.

Example 18

Several compounds of the invention of formula (I), being prepared asformerly reported, were also characterized by means of HPLC/Masstechniques, hence through retention time (r.t.) and Mass [M+H]^(+.)

The operative conditions are reported below:

HPLC/MS Method 1

The HPLC equipment consisted of a Waters Alliance HT 2795 HPLC systemequipped with a 996 Waters PDA detector and Micromass mod. ZQ singlequadrupole mass spectrometer, equipped with an electrospray (ESI) ionsource. Instrument control, data acquisition and data processing wereprovided by Millennium 4.0 and MassLynx 3.5 software.

HPLC was carried out at 25° C. at a flow rate of 1 mL/min using a RP18Waters X Terra (4.6×50 mm, 5 μm) column. Mobile phase A was ammoniumacetate 5 mM buffer (pH 5.2 with acetic acid/acetonitrile 95:5), andMobile phase B was H₂O/acetonitrile (5:95); the gradient was from 10 to90% B in 4 min then hold 90% B 1 minute. The injection volume was 10microL.

The mass spectrometer was operated in positive and in negative ion mode,the capillary voltage was set up at 3.48 kV for (ES+) and 2.76 kV for(ES−); the source temperature was 120° C.; cone was 15 V; full scan,mass range from 100 to 800 amu was set up.

HPLC/MS Method 2

The HPLC equipment consisted of a Waters Alliance HT 2795 HPLC systemequipped with a 996 Waters PDA detector and Micromass mod. ZQ singlequadrupole mass spectrometer, equipped with an electrospray (ESI) ionsource. Instrument control, data acquisition and data processing wereprovided by Millennium 4.0 and MassLynx 3.5 software.

HPLC was carried out at 25° C. at a flow rate of 1 mL/min using a RP18Waters X Terra (4.6×50 mm, 5 μm) column. Mobile phase A was ammoniumacetate 5 mM buffer (pH 5.2 with acetic acid/acetonitrile 95:5), andMobile phase B was H₂O/acetonitrile (5:95); the gradient was from 10 to90% B in 8 min then hold 100% B 2 minute. The injection volume was 10microL.

The mass spectrometer was operated in positive and in negative ion mode,the capillary voltage was set up at 3.48 kV for (ES+) and 2.76 kV for(ES−); the source temperature was 120° C.; cone was 15 V; full scan,mass range from 100 to 800 amu was set up.

TABLE IV HPLC N^(o) Code r.t. (min) [M + H]⁺ Method 10 A1-Z-B8 2.5 552 111 A1-Z-B9 2.1 518 1 12 A1-Z-B10 1.9 533 1 13 A1-Z-B11 2.4 507 1 14A1-Z-B12 2.1 503 1 15 A1-Z-B13 2.2 518 1 16 A1-Z-B14 2.5 523 1 17A1-Z-B15 2.1 503 1 18 A1-Z-B16 2.3 487 1 19 A1-Z-B17 2.7 549 1 20A1-Z-B18 2.4 563 1 21 A1-Z-B19 2.4 507 1 22 A1-Z-B20 2.1 503 1 23A1-Z-B21 2.4 552 1 24 A1-Z-B22 2.1 517 1 25 A1-Z-B23 2.2 518 1 26A1-Z-B24 2.1 533 1 27 A1-Z-B25 2.2 491 1 28 A1-Z-B26 2.1 516 1 29A1-Z-B27 2.2 487 1 30 A1-Z-B28 2.2 491 1 31 A1-Z-B29 2.3 487 1 32A1-Z-B30 2.8 545 1 33 A1-Z-B31 1.7 551 1 34 A1-Z-B32 2.7 557 1 35A1-Z-B33 2.3 527 1 36 A1-Z-B34 2.6 515 1 37 A1-Z-B35 2.9 609 1 38A1-Z-B36 2.6 542 1 39 A1-Z-B37 2.2 491 1 40 A1-Z-B38 2.3 525 1 41A1-Z-B39 2.3 519 1 42 A1-Z-B40 2.6 563 1 43 A1-Z-B41 3.0 609 1 44A1-Z-B42 2.4 541 1 45 A1-Z-B43 2.7 586 1 46 A1-Z-B44 2.3 509 1 47A1-Z-B45 2.2 509 1 48 A1-Z-B46 2.3 509 1 49 A1-Z-B47 2.6 541 1 50A1-Z-B48 1.9 563 1 51 A1-Z-B49 2.6 542 1 52 A1-Z-B50 2.5 523 1 53A1-Z-B51 2.1 533 1 54 A1-Z-B52 2.3 507 1 55 A1-Z-B53 2.4 599 1 56A1-Z-B54 2.3 509 1 57 A1-Z-B55 2.2 563 1 58 A4-Z-B1 2.3 512 1 63 A7-Z-B12.2 458 1 64 A8-Z-B1 2.4 458 1 65 A9-Z-B1 2.3 496 1 66 A10-Z-B1 2.9 5001 67 A11-Z-B1 2.6 479 1 68 A12-Z-B1 1.9 410 1 69 A13-Z-B1 2.2 469 1 70A14-Z-B1 2.3 489 1 71 A15-Z-B1 2.1 489 1 72 A16-Z-B1 2.3 462 1 73A17-Z-B1 2.2 444 1 74 A18-Z-B1 2.1 424 1 75 A19-Z-B1 2.4 470 1 76A20-Z-B1 2.7 512 1 77 A21-Z-B1 2.6 523 1 78 A22-Z-B1 2.2 488 1 79A23-Z-B1 2.3 474 1 80 A24-Z-B1 2.2 474 1 81 A25-Z-B1 1.8 408 1 82A26-Z-B1 1.9 434 1 83 A27-Z-B1 2.3 513 1 84 A28-Z-B1 2.3 489 1 85A29-Z-B1 1.7 394 1 86 A30-Z-B1 2.1 450 1 87 A31-Z-B1 2.3 480 1 88A32-Z-B1 2.3 462 1 89 A33-Z-B1 2.1 504 1 90 A34-Z-B1 2.5 523 1 91A35-Z-B1 2.7 528 1 92 A36-Z-B1 2.2 464 1 93 A36-Z-B5 2.2 431 1 94A37-Z-B5 2.3 455 1 95 A38-Z-B5 2.7 479 1 96 A39-Z-B5 1.6 412 1 97A40-Z-B5 2.7 439 1 98 A41-Z-B5 2.6 461 1 99 A42-Z-B5 2.4 443 1 100A43-Z-B5 2.3 485 1 101 A44-Z-B5 2.3 455 1 102 A45-Z-B5 2.6 447 1 103A46-Z-B5 2.6 445 1 104 A47-Z-B5 2.3 429 1 105 A48-Z-B5 2.4 441 1 106A4-Z-B5 2.4 479 1 107 A49-Z-B5 2.5 447 1 108 A50-Z-B5 2.4 447 1 109A51-Z-B5 2.4 447 1 110 A52-Z-B5 2.5 425 1 111 A53-Z-B5 2.9 480 1 112A54-Z-B5 2.6 471 1 113 A55-Z-B5 2.7 467 1 114 A56-Z-B5 2.8 495 1 115A57-Z-B5 3.1 497 1 116 A58-Z-B5 2.1 389 1 117 A59-Z-B5 2.4 417 1 118A60-Z-B5 2.5 504 1 119 A61-Z-B5 2.7 467 1 120 A62-Z-B5 3.0 493 1 121A63-Z-B5 2.0 430 1 122 A64-Z-B5 2.3 403 1 123 A65-Z-B5 2.4 454 1 124A66-Z-B5 1.0 429 1 125 A67-Z-B5 1.9 419 1 126 A68-Z-B5 1.5 496 1 129A1-Z-B57 4.2 543 2 130 A1-Z-B58 4.1 553 2 131 A1-Z-B59 3.5 502 2 132A1-Z-B60 3.8 558 2 133 A1-Z-B61 3.9 502 2 134 A1-Z-B62 4.3 543 2 135A1-Z-B63 4.2 543 2 136 A1-Z-B64 3.7 526 2 137 A1-Z-B65 3.1 524 2 138A1-Z-B66 4.1 542 2 139 A1-Z-B67 3.8 508 2 140 A1-Z-B68 3.2 504 2 141A1-Z-B69 3.4 488 2 142 A1-Z-B70 3.5 492 2 143 A1-Z-B71 3.2 492 2 144A1-Z-B72 3.2 510 2 145 A1-Z-B73 4.4 558 2 146 A1-Z-B74 3.1 502 2 147A1-Z-B75 3.0 504 2 148 A1-Z-B76 3.0 610 2 149 A1-Z-B77 3.4 504 2 150A1-Z-B78 3.6 508 2 151 A1-Z-B79 4.0 524 2 152 A1-Z-B80 3.7 516 2 153A1-Z-B81 4.1 558 2 154 A1-Z-B82 3.9 560 2 155 A1-Z-B83 3.7 510 2 156A1-Z-B84 3.4 518 2 157 A1-Z-B85 3.8 530 2 158 A1-Z-B86 4.1 522 2 159A1-Z-B87 3.7 546 2 160 A1-Z-B88 3.4 532 2 161 A1-Z-B89 3.2 522 2 162A1-Z-B90 3.9 532 2 163 A1-Z-B91 7.2 576 2 164 A1-Z-B92 3.1 492 2 165A1-Z-B93 3.1 516 2 166 A1-Z-B94 3.1 488 2 167 A1-Z-B95 2.5 534 2 168A1-Z-B96 3.7 530 2 169 A1-Z-B97 2.8 534 2 170 A1-Z-B98 4.6 576 2 171A1-Z-B99 4.2 560 2 172 A1-Z-B100 4.5 566 2 173 A1-Z-B101 3.0 564 2 174A1-Z-B102 3.5 520 2 175 A1-Z-B103 3.9 502 2 176 A1-Z-B104 3.2 560 2 177A1-Z-B105 3.2 499 2 178 A1-Z-B106 3.4 502 2 179 A1-Z-B107 4.3 542 2 180A1-Z-B108 3.5 542 2 181 A1-Z-B109 3.5 510 2 182 A1-Z-B110 3.8 508 2 183A1-Z-B111 2.2 576 1 184 A1-Z-B112 2.5 510 1 187 A51-Z-B1 2.3 480 1 188A52-Z-B1 2.4 458 1 189 A53-Z-B1 2.8 513 1 190 A55-Z-B1 2.7 500 1 191A56-Z-B1 2.7 528 1 192 A57-Z-B1 3.0 530 1 193 A58-Z-B1 2.0 422 1 194A59-Z-B1 2.3 450 1 195 A60-Z-B1 2.4 537 1 196 A61-Z-B1 2.6 500 1 197A62-Z-B1 2.2 526 1 198 A63-Z-B1 2.0 463 1 199 A64-Z-B1 2.2 436 1 200A66-Z-B1 2.3 462 1 201 A67-Z-B1 1.8 452 1 202 A68-Z-B1 2.5 529 1 203A7-Z-B5 2.3 425 1 204 A8-Z-B5 2.5 425 1 205 A9-Z-B5 2.4 463 1 206A10-Z-B5 3.0 467 1 207 A11-Z-B5 2.6 445 1 208 A12-Z-B5 2.0 377 1 209A13-Z-B5 2.3 436 1 210 A14-Z-B5 2.4 456 1 211 A15-Z-B5 2.2 456 1 212A16-Z-B5 2.4 429 1 213 A70-Z-B5 1.5 349 1 214 A17-Z-B5 2.3 411 1 215A18-Z-B5 2.2 391 1 216 A19-Z-B5 2.5 437 1 217 A20-Z-B5 2.8 479 1 218A21-Z-B5 2.7 490 1 219 A22-Z-B5 2.3 455 1 220 A23-Z-B5 2.4 441 1 221A24-Z-B5 2.3 441 1 222 A25-Z-B5 1.9 375 1 223 A26-Z-B5 2.0 401 1 224A27-Z-B5 2.4 479 1 225 A28-Z-B5 2.4 456 1 226 A29-Z-B5 1.8 361 1 227A30-Z-B5 2.2 417 1 228 A31-Z-B5 2.4 447 1 229 A32-Z-B5 2.4 429 1 230A33-Z-B5 2.2 471 1 231 A34-Z-B5 2.7 490 1 232 A35-Z-B5 2.8 495 1 259A1-Z-B113 4.1 546 2 260 A1-Z-B114 3.3 480 2 261 A1-Z-B115 2.4 493 2 262A1-Z-B116 3.1 499 2 263 A1-Z-B117 3.1 480 2 264 A1-Z-B118 4.3 543 2 265A1-Z-B119 3.3 568 2 266 A1-Z-B120 2.8 509 2 267 A1-Z-B121 3.0 526 2 268A1-Z-B122 3.1 571 2 269 A1-Z-B123 3.8 578 2 270 A1-Z-B124 3.5 587 2 271A1-Z-B125 3.6 577 2 272 A1-Z-B126 3.0 621 2 273 A1-Z-B127 3.8 579 2 274A1-Z-B128 4.2 626 2

1. A compound of formula (I):

wherein: R is hydrogen or an optionally further substituted groupselected from: saturated or unsaturated, straight or branched C₁-C₆alkyl, C₃-C₆ cycloalkyl, heterocyclyl and aryl; A is CH₂ or NH; Ar is anoptionally substituted aryl, provided that when A is CH₂ and Ar isphenyl then R is other than 3-bromophenyl, 4-fluorophenyl,4-tert-butylphenyl, cyclopropyl or 2-naphthyl and when A is CH₂ and Aris thiophene then R is other than 3-bromophenyl, 4-fluorophenyl,4-tert-butylphenyl, cyclopropyl, 2-naphthyl or benzyl; and isomers,tautomers, hydrates, solvates, complexes, metabolites, prodrugs,carriers, N-oxides and pharmaceutically acceptable salts thereof.
 2. Acompound of formula (I) as defined in claim 1 wherein: R is a C₁-C₆alkyl substituted by heterocyclyl or aryl, or an optionally furthersubstituted heterocyclyl or aryl.
 3. A compound of formula (I) asdefined in claims 1 or 2 wherein: R is heterocyclylmethyl, arylmethyl,or an optionally further substituted heterocyclyl or aryl; Ar is anoptionally substituted phenyl, thienyl or furyl.
 4. A compound offormula (I) as defined in claims 1 to 3 wherein: R is an optionallyfurther substituted heterocyclyl or aryl.
 5. A compound of formula (I)as defined in claims 1 to 4 wherein: Ar is a group selected from:

wherein R₁, R′₁ and R″₁ are independently hydrogen, halogen, nitro, oxogroups (═O), cyano, C₁-C₆ alkyl, polyfluorinated alkyl, polyfluorinatedalkoxy, hydroxyalkyl, hydroxy, alkoxy, alkylcarbonyloxy, carboxy,alkoxycarbonyl, aryloxycarbonyl, amino, ureido, alkylamino,dialkylamino, alkylcarbonylamino, heterocyclylcarbonylamino,alkylsulfonylamino, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl,alkylsulfonyl, aminosulfonyl, and alkylthio.
 6. A compound of formula(I) as defined in claims 1 to 5 wherein: Ar is a group of formula

wherein R₁ and R′₁ are as defined in claim
 5. 7. A compound of formula(I) as defined in claims 1 to 6 wherein: R is a group selected from:

wherein R₂ is selected from: C₁-C₆ alkyl, halogen, nitro, oxo groups(═O), cyano, polyfluorinated alkyl, polyfluorinated alkoxy, alkenyl,alkynyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, cycloalkyl,hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylenedioxy,alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy,heterocyclylcarbonyloxy, alkylideneaminooxy, carboxy, alkoxycarbonyl,aryloxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, amino,ureido, alkylamino, dialkylamino, arylamino, diarylamino,heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino,heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl,alkoxycarbonylamino, hydroxyaminocarbonyl alkoxyimino,alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino,formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl,heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,heterocyclylaminosulfonyl, arylthio, alkylthio phosphonate andalkylphosphonate; Ar is a group of formula

wherein R₁ and R′₁ are as defined in claim
 5. 8. Any specific compoundof formula (I) as defined in claim 1, optionally in the form ofhydrates, solvates, complexes, metabolites, prodrugs, carriers, N-oxidesand pharmaceutically acceptable salts, selected from the groupconsisting of:N-(2,6-dichlorophenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxamide(A1-Z-B1);N-[6,6-dimethyl-5-(phenylacetyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B2);N-(2,6-difluorophenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxamide(A1-Z-B3);N-{5-[(3,5-difluorophenyl)acetyl]-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B4);N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B5);N-(2,6-dichlorophenyl)-6,6-dimethyl-3-{[3-(4-methylpiperazin-1-yl)benzoyl]amino}-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxamide(A2-Z-B1);N-{5-[(2,6-dichlorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B7);N-{6,6-dimethyl-5-[(2-nitrophenyl)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B9);N-{5-[(2-methoxyphenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B15);N-{5-[(3-chlorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B19);N-{5-[(3-methoxyphenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B20);N-{5-[(3-bromophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B21);N-{5-[(4-fluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B25);N-{6,6-dimethyl-5-[(2-methylphenyl)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B27);N-{5-[(3-fluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B28);N-{6,6-dimethyl-5-[(3-methylphenyl)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B29);N-{6,6-dimethyl-5-[(2,3,6-trifluorophenyl)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B33);N-[5-(mesitylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B34);N-{5-[(2,4-dichlorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B36);N-{5-[(2-fluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B37);N-{5-[(2-chloro-6-fluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B38);N-(6,6-dimethyl-5-{[2-(trifluoromethyl)phenyl]acetyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B42);N-(6,6-dimethyl-5-{[2-nitro-4-(trifluoromethyl)phenyl]acetyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B43);N-{5-[(3,4-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B44);N-{5-[(2,5-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B45);N-{5-[(2,4-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B46);N-{5-[(2-chlorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B52);N-{5-[(2-iodophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B53);N-{5-[(2,3-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B54);N-{6,6-dimethyl-5-[(2,4,6-trimethoxyphenyl)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B55);N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-3-(4-methylpiperazin-1-yl)benzamide(A2-Z-B5);N-[6,6-dimethyl-5-(2-thienylacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide(A1-Z-B56);4-({5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}carbamoyl)benzoicacid (A6-Z-B5);N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[(4-methylbenzoyl)amino]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A8-Z-B1);3-[(4-chlorobenzoyl)amino]-N-(2,6-dichlorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A11-Z-B1);N-(2,6-dichlorophenyl)-3-[(3-fluorobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A16-Z-B1);3-(benzoylamino)-N-(2,6-dichlorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A17-Z-B1);N-(2,6-dichlorophenyl)-6,6-dimethyl-3-{[(2E)-3-phenylprop-2-enoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A19-Z-B1);N-(2,6-dichlorophenyl)-3-[(4-methoxybenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A24-Z-B1);N-(2,6-dichlorophenyl)-3-(2-furoylamino)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A26-Z-B1);N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[(2-thienylcarbonyl)amino]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A30-Z-B1);N-(2,6-dichlorophenyl)-3-[(2,4-difluorobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A31-Z-B1);N-(2,6-dichlorophenyl)-3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A32-Z-B1);N-(2,6-dichlorophenyl)-3-[(3,4-dimethoxybenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A33-Z-B1);N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-2-fluorobenzamide(A47-Z-B5);N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-(dimethylamino)benzamide(A65-Z-B5);4-({5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}carbamoyl)benzoicacid (A6-Z-B1);N-(2,5-dimethylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B59);6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-N-[2-(trifluoromethoxy)phenyl]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B60);N-(2,6-diisopropylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B73);N-(2,6-dimethylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B74);N-(2-methoxyphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B77);N-(2-chlorophenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B78);N-(2-isopropylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B80);N-(2,6-diethylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B85);N-(2-chloro-6-methylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B89);N-(2-fluorophenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B92);6,6-dimethyl-N-(2-methylphenyl)-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B94);N-(2,6-dimethoxyphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B95);N-(2-tert-butylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B96);6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-N-[2-(methylthio)phenyl]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B102); formicacid—N-[2-fluoro-6-(trifluoromethyl)phenyl]-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxamide(1:1) (A1-Z-B104);N-(2-ethylphenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B106);6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-N-[2-(trifluoromethyl)phenyl]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B108);N-[2-chloro-6-(trifluoromethyl)phenyl]-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A1-Z-B111); methyl3-({5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}carbamoyl)benzoate(A89-Z-B1);N-(2,6-dichlorophenyl)-3-[(2,5-difluorobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A51-Z-B1);N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[(3-methylbenzoyl)amino]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A52-Z-B1);3-[(1-benzothien-2-ylcarbonyl)amino]-N-(2,6-dichlorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A55-Z-B1);N-(2,6-dichlorophenyl)-3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A66-Z-B1);3-{[(4-bromo-2-thienyl)carbonyl]amino}-N-(2,6-dichlorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A68-Z-B1);N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-3-fluorobenzamide(A16-Z-B5);N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}benzamide(A17-Z-B5);N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-methoxybenzamide(A24-Z-B5);N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-2-furamide(A26-Z-B5);N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}thiophene-2-carboxamide(A30-Z-B5);N-{5-[(2,6-difluorophenyl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-N′-(1-methylpiperidin-4-yl)terephthalamide(A72-Z-B5);N-{5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-N′-[3-(dimethylamino)propyl]terephthalamide(A71-Z-B1);N-{5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-N′-(1-methylpiperidin-4-yl)terephthalamide(A72-Z-B1);N-{5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}terephthalamide(A75-Z-B1);N-{5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-N′-hydroxyterephthalamide(A76-Z-B1);N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[(4-{[(1-methylpiperidin-4-yl)carbonyl]amino}benzoyl)amino]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A77-Z-B1);N-(2,6-dichlorophenyl)-6,6-dimethyl-3-{[4-(methylsulfonyl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A78-Z-B1);3-({5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}carbamoyl)benzoicacid (A79-Z-B1);N-{5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}isophthalamide(A80-Z-B1);N-{5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-N′-(1-methylpiperidin-4-yl)isophthalamide(A81-Z-B1);N-{5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-N′-hydroxyisophthalamide(A82-Z-B1);N-(2,6-dichlorophenyl)-6,6-dimethyl-3-[(3-{[(1-methylpiperidin-4-yl)carbonyl]amino}benzoyl)amino]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A83-Z-B1);3-[(3-aminobenzoyl)amino]-N-(2,6-dichlorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A84-Z-B1);3-[(4-aminobenzoyl)amino]-N-(2,6-dichlorophenyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A85-Z-B1);N-(2,6-dichlorophenyl)-6,6-dimethyl-3-{[4-(4-methylpiperazin-1-yl)-3-nitrobenzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A86-Z-B1);N-(2,6-dichlorophenyl)-3-[(4-fluoro-3-nitrobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A87-Z-B1);diethyl[4-({5-[(2,6-dichlorophenyl)carbamoyl]-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}carbamoyl)phenyl]phosphonate(A91-Z-B1);N-(3,5-dimethylisoxazol-4-yl)-6,6-dimethyl-3-({[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamidetrifluoroacetate (A1-Z-B115);N-(2-cyanophenyl)-6,6-dimethyl-3-({[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamidetrifluoroacetate (A1-Z-B116);N-(2-chloropyridin-3-yl)-6,6-dimethyl-3-({[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamidetrifluoroacetate (A1-Z-B120);N-(2-bromo-6-fluorophenyl)-6,6-dimethyl-3-({[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamidetrifluoroacetate (A1-Z-B122);N-(2,6-dichloro-4-nitrophenyl)-6,6-dimethyl-3-({[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamidetrifluoroacetate (A1-Z-B124);N-[2,6-dichloro-4-(trifluoromethoxy)phenyl]-6,6-dimethyl-3-({[4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamidetrifluoroacetate (A1-Z-B128);N-(2,6-dichlorophenyl)-3-[({2-[(2-methoxyethyl)amino]-4-(4-methylpiperazin-1-yl)phenyl}carbonyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A95-Z-B1), andN-(2,6-dichlorophenyl)-3-({[2-{[(1S)-2-methoxy-1-methylethyl]amino}-4-(4-methylpiperazin-1-yl)phenyl]carbonyl}amino)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide(A96-Z-B1).
 9. A process for preparing a compound of formula (I) asdefined in claim 1, either by pathway A or pathway B, characterized inthat pathway A comprises: a) reacting any of the two regioisomeric formsof the compound of formula (II)

wherein Q is a suitable protecting group with a compound of formula(III)R—CO—Y   (III) wherein R is as defined in claim 1 and Y is a halogenatom, so as to obtain the compound of formula (IV)

wherein R is as defined in claim 1 and Q is a suitable protecting group;b) deprotecting the amino group of the compound of formula (IV) so as toobtain the corresponding derivative of formula (V)

wherein R is as defined in claim 1; c) reacting the compound of formula(V) according to any one of the alternative steps c.1), c.2), c.3): c1)with an acid of formula (VI),Ar—A—COOH   (VI) wherein Ar is as defined in claim 1 and A is CH₂, inthe presence of a suitable condensing agent so as to obtain a compoundof formula (VII)

wherein R and Ar are as defined in claim 1 and A is CH₂; c.2) with anisocyanate of formula (VIII)Ar—NCO   (VIII) wherein Ar is as defined in claim 1, so as to obtain acompound of formula (VII) wherein R and Ar are as defined in claim 1 andA is NH; c.3) with an amine of formula (IX)Ar—NH₂   (IX) wherein Ar is as defined in claim 1, in the presence oftriphosgene, di-tert-butyl dicarbonate or of a suitable chloroformate soas to obtain a compound of formula (VII) wherein R and Ar are as definedabove and A is NH; d) reacting the compound of formula (VII) preparedaccording to any one of steps from c.1) to c.3) under basic conditions,so as to obtain the desired derivative of formula (I) defined in claim 1and, optionally, e) converting them into other compounds of formula (I)and/or into hydrates, solvates, complexes, metabolites, prodrugs,carriers, N-oxides and pharmaceutically acceptable salts thereof;pathway B comprises: f) removing the amino protecting group Q fromcompound of formula (II) as defined above, so to obtain a compound offormula (X);

g) reacting compound of formula (X) accordingly to any one of thealternative steps c.1), c.2) or c.3) as defined above, to obtain acompound of formula (XI)

wherein Ar and A are as defined in claim 1; h) reacting compounds offormula (XI) as defined above, with compounds of formula (III) asdefined above, so to obtain compounds of formula (VII) as defined above;i) reacting the resulting compound of formula (VII) under basicconditions, so as to obtain the corresponding derivative of formula (I)as defined in claim 1; and, optionally, j) converting them into othercompounds of formula (I), and/or into hydrates, solvates, complexes,metabolites, prodrugs, carriers, N-oxides and pharmaceuticallyacceptable salts thereof.
 10. A method for treating a disease caused byand/or associated with a dysregulated protein kinase activity whichcomprises administering to a mammal in need thereof an effective amountof a compound of formula (I) as defined in claim
 1. 11. The methodaccording to claim 10 for treating a disease caused by and/or associatedwith a dysregulated PLK-1, Aurora-2 or Cdk2/cyclin A activity.
 12. Themethod according to claim 11 for treating a disease caused by and/orassociated with a dysregulated PLK-1 activity.
 13. The method accordingto claim 10 wherein the disease is selected from the group consisting ofcancer, cell proliferative disorders, viral infections, autoimmune andneurodegenerative disorders.
 14. The method according to claim 13wherein the cancer is selected from the group consisting of carcinomasuch as bladder, breast, colon, kidney, liver, lung, including smallcell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach,cervix, thyroid, prostate, and skin, including squamous cell carcinoma;hematopoietic tumors of lymphoid lineage including leukaemia, acutelymphocitic leukaemia, acute lymphoblastic leukaemia, B-cell lymphoma,T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma and Burkett's lymphoma; hematopoietic tumors of myeloidlineage, including acute and chronic myelogenous leukemias,myelodysplastic syndrome and promyelocytic leukaemia; tumors ofmesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumorsof the central and peripheral nervous system, including astrocytomaneuroblastoma, glioma and schwannomas; other tumors, including melanoma,seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum,keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma.
 15. Themethod according to claim 13 wherein the cell proliferative disorder isselected from the group consisting of benign prostate hyperplasia,familial adenomatosis polyposis, neurofibromatosis, psoriasis, vascularsmooth cell proliferation associated with atherosclerosis, pulmonaryfibrosis, arthritis, glomerulonephritis and post-surgical stenosis andrestenosis.
 16. The method according to claim 13 for treating viralinfections in HIV-infected individuals.
 17. The method according toclaim 10 which provides tumor angiogenesis and metastasis inhibition aswell as the treatment of organ transplant rejection and host versusgraft disease.
 18. The method according to claim 10 further comprisingsubjecting the mammal in need thereof to a radiation therapy orchemotherapy regimen in combination with at least one cytostatic orcytotoxic agent.
 19. The method according to claim 10 wherein the mammalin need thereof is a human.
 20. A method for inhibiting the activity poPLK-1 protein which comprises contacting said protein with an effectiveamount of a compound as defined in claim
 1. 21. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof, as definedin claim 1, and at least one pharmaceutically acceptable excipient,carrier and/or diluent.
 22. A pharmaceutical composition according toclaim 21 further comprising one or more chemotherapeutic agents.
 23. Aproduct or kit comprising a compound of formula (I) or apharmaceutically acceptable salt thereof, as defined in claim 1, orpharmaceutical compositions thereof as defined in claim 21 and one ormore chemotherapeutic agent, as a combined preparation for simultaneous,separate or sequential use in anticancer therapy.
 24. A compound offormula (I) or a pharmaceutically acceptable salt thereof, as defined inclaim 1, for use as a medicament.
 25. A compound of formula (I) or apharmaceutically acceptable salt thereof, as defined in claim 1, for usein a method for treating cancer.
 26. Use of a compound of formula (I) ora pharmaceutically acceptable salt thereof, as defined in claim 1, inthe manufacture of a medicament with anticancer activity.